Dissociation between Dyspnea and Respiratory Effort1 - 4
BARBARA H. DEMEDIUK, HAROLD MANNING, JENNIFER LILLY, VLADIMIR FENCL, STEVEN E. WEINBERGER, J. WOODROW WEISS, and RICHARD M. SCHWARTZSTEIN
Introduction
Studies of voluntary muscles suggest that the sense of muscular effort arises from perception of the outgoing command from the motor cortex (1-3). For the respiratory muscles, this sense of muscular effort may contribute to the sensation of breathlessness.El-Manshawi and colleagues (4) studied normal subjects during exercise and found that breathlessness was related to several indices of respiratory muscle effort. They concluded that the sense of effort was "ideally suited to mediate the sensation of breathlessness." Killian and coworkers (1) demonstrated that perceived breathlessness and perceived effort closely paralleled one another during breathing with a range of elastic loads, and when the inspiratory muscles wereweakened by an increase in lung volume. Indeed, on the basis of these findings, Killian and colleagues concluded that "breathlessness and effort are identical and mediated by the same mechanism." However, under some circumstances, both clinical and experimental, the relationship between breathlessness and effort is less apparent. In our experience, patients with pulmonary embolism or pulmonary hypertension may report breathlessness that appears to be out of proportion to factors normally associated with respiratory effort, e.g., minute ventilation and changes in pulmonary mechanics. Individuals with severe lung disease may report breathlessness when attempting to suppress ventilation briefly while eating or speaking. Similarly, when normal subjects suppress their ventilation to a level below that dictated by chemical drive, breathlessness increases without corresponding increases in indices of respiratory muscle effort (5). Because of these apparent discrepancies, we sought to examine further the relationship between breathlessness and respiratory effort. Moreover, because the respiratory musclesare unique among the skeletal muscles in having both cortical and brain stem control, we hypothesized 1222
SUMMARY Breathlessness induced by hypercapnia may be related to the sensation of respiratory effort or to the central or peripheral effects of CO2 , To examine the relationship among breathlessness, respiratory effort, and hypercapnia, we studied eight normal naive subjects. By using a visual feedback system, subjects maintained a constant ventilation of 50-60 Umin. PETC0 2 was held at 40 mm Hg during the first 2 min of each trial (control period), then for 4 min (test period) was either kept at 40 mm Hg or elevated to 50 mm Hg. At the end of each control and test period, subjects were asked to give separate ratings for dyspnea (an unpleasant urge to breathe) and for the sense of respiratory effort (analogous to lifting a weight) on a 50-cm visual analog scale. Hypercapnia was associated with a significant reduction In effort ratings (-7.3 ± 6.4, mean ± SO, P < 0.05) and a concomitant Increase In dyspnea ( +6.6 ± 6.0, P < 0.05). Weconclude that dyspnea associated with hypercapnia Is dissociated from changes In respiratory effort, and that CO2 has a direct central effect that leads to breathlessness. Our data also suggest that the sense of effort at a given level of ventilation Is less when the ventilation is the result of "reflex" stimuli to breathe rather than "volunAM REV RESPIR DIS 1992; 146:1222-1225 tary" signals to the respiratory muscles.
that the sense of respiratory muscle effort would vary with the origin of the respiratory motor command. Methods
Subjects Westudied five male and three female volunteers aged 27 to 34 years. Subjects were excluded if they had a history of cardiac or pulmonary disease, migraine headaches, or seizures. All of the subjects were naive to the purpose of the study. The protocol was approved by the Committee on ClinicalInvestigation at Beth IsraelHospital, and informed consent was obtained from all subjects in accordance with the guidelines of this committee.
Techniques Breathingcircuit. Each subject was seated in a straight-back chair that allowed position to be fixed. The subjects wore noseclips and breathed through an Otis-McKerrow valve connected to a Fleish pneumotachograph (no. 3). The inspiratory limb of the circuit was attached to a differential manometer calibrated to ventilation (6). The visual display from this device was used to target ventilation. Measurement ofrespiratory variables. Inspiratory flow was measured with the pneumotachograph, and inspired tidal volume (VT) was obtained by electrical integration of the flow signal (Hewlett Packard 8815A;Hewlett Packard, Waltham, MA). Inspiratory time (TI), total respiratory cycle time (not), and frequency (f) were measured from the flow tracing. Pairs of magnetometer coils were
placed anteroposteriorly on the rib cage at the levelof the midsternum and on the abdomen just above the umbilicus.The magnetometers were calibrated by the isovolume method (7). The relative contribution of the rib cage compartment to total ventilation was obtained by dividing the amplitude of the rib cage signal by the sum of the rib cage and abdominal signals. In order to determine changes in functional residualcapacity (PRC), the signals from the magnetometer coils were summed and then converted to an absolute volume by calibration with the volume obtained from integration of the flow signal. End-tidal CO 2(PETC02) was measured at the mouth with a mass spectrometer (Perkin Elmer 1100; Perkin-Elmer, Pomona, CA). All signals were continuously recorded on a strip chart recorder (Hewlett Packard 7758B) for subsequent analysis.
(Received in original form May 8, 1991 and in revised form March 6, 1992) 1 From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. 2 Supported by the Pulmonary SCOR grant HL-19170. 3 Presented in part at the Annual Meeting of the American Thoracic Society, Boston, Massachusetts, May 1990. 4 Correspondence and requests for reprints should be addressed to Richard M. Schwartzstein, M.D., Pulmonary Unit, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215.
1223
DISSOCIATION BETWEEN DYSPNEA AND RESPIRATORY EFFORT
Assessment of ventilatory responsiveness to CO2 • Subjects breathed air while 100% CO2 was added to the inspiratory limb of the circuit at a rate sufficient to maintain PETC 02 constant at 55 mm Hg for 5 min. Because we wanted to target subjects to a levelof ventilation that would require at least a moderate levelof respiratory effort (seelater, under Protocol), we excluded from the study subjects whose ventilation at the end of the 5-min period was less than 250/0 oftheir predicted maximal voluntary ventilation. Quantitation of breathlessness and respiratory effort. Each subject was given written instructions to read. The subjects were told that the inspired concentrations of carbon dioxide and/or oxygen might vary, and that at various intervals they would be asked to rate their respiratory sensations. Breathlessness was defined as an "unpleasant urge to breathe." Effort was described as a sensation analogous to the one that accompanies the volitional act oflifting a weight (as compared with the sensation associated with the muscular contraction elicited by tapping a tendon). At the end of each test period, subjects were asked to rate these sensations using a visual analog scale that consisted of a 50-cm bar with a sliding disk attached. The markings on the scale were visible only to the investigators. The left end of the scale was defined as no effort or breathlessness, and the right end was defined as maximal effort or breathlessness. The subject was told to move the disk a distance proportional to the intensity of the sensation, and for each rating period, the distance of the disk from the origin (in centimeters) was recorded and taken as the subject's rating for that period. Protocol The subjects' PETc02 was maintained at 55 mm Hg for 5 min, and their ventilation during the final minute was recorded. After a 5-min rest, the subjects wereinstructed to target their ventilation to a level 5 to 10 L/min greater than that achieved spontaneously at the end of the 5 min at PETc02 = 55 mm Hg. We chose this higher level of ventilation to eliminate any need for the subjects to suppress their ventilation during the subsequent repeated periods of hypercapnia. Each trial lasted 6 min and consisted of an initial 2-min control period followed by a 4-min test period. The subjects maintained their ventilation at the assigned target throughout the entire trial. For each control period, PETC02 was held constant at 40 mm Hg, and during the final 30 s, the subjects were asked to provide separate ratings first for effort and then for breathlessness. The VAS was reset to zero between ratings. During the test period, PETC02 was either maintained at 40 mm Hg (Condition A) or increased to 50 mm Hg (Condition B). During the final 30 s of the test period, the subjects were shown first their effort and then their breathlessness ratings from the control period and asked to give a second set of ratings. There werea total of sixtrials, three using
Condition A and three using Condition B, scheduled at random. There was a to-min rest period between the trials, all of which were conducted at one sitting. At the conclusion of each trial the subjects were asked to comment on their sensations during the study.
(19.6 ± 5.7 em for Condition A versus 18.6 ± 6.0 em for Condition B). However, when PETc02 was maintained at 40 mm Hg for the test period (Condition A), effort ratings increased, whereas when PETC02 was increased to 50 mm Hg during the test period (Condition B), effort ratings decreased (mean change in effort ratings 3.3 ± 6.8 versus -4.0 ± 5.4, respectively, p < 0.05). The range in ratings for effort was 0 to 37. Figure 3 demonstrates the relative changes in effort and breathlessness ratings for Condition A and B. When PETc02 was maintained at 40 mm Hg during the test period (Condition A), both effort and breathlessness ratings increased. In contrast, when PETCO 2 was increased to 50 mm Hg during the test period (Condition B), effort ratings decreased while breathlessness ratings increased.
Data Analysis For each trial we calculated the differences between the control and rest periods for the breathlessness and effort ratings and the various respiratory variables. The differences between Conditions A and B were then compared using a two-tailed paired ttest. A p value of < 0.05 was considered significant. Data are expressed as mean ± So. Results
Breathlessness Ratings The mean ratings for each subject under the control and test conditions as well as the mean ratings for the group as a whole are shown in figure 1. There was no significant difference in mean breathlessness ratings between the two control periods (9.8 ± 10.5 em for Condition A versus 9.3 ± 8.8 em for Condition B). Although breathlessness ratings increased from the control to the test period in both Conditions A and B, the mean increase in breathlessness rating was significantly greater for Condition B (9.4± 7.2 versus 3.0 ± 6.0, p < 0.05). The range in ratings for breathlessness was 0 to 45.
Effort Ratings The mean ratings for each subject under the control and test conditions as well as the mean ratings for the group as a whole are shown in figure 2. There was no significant difference between the two control periods in mean effort ratings
Respiratory Variables (table 1) The respiratory variables minute ventilation, tidal volume, frequency, mean inspiratory flow, duty cycle, and the relative contribution of the rib cage compartment to total ventilation did not vary significantly throughout the experimental protocol. There was a small but statistically significant difference in the change in FRC between Condition A and Condition B (p < 0.05), i.e., there was a greater decrease in FRC during Condition B.
Subjective Comments Two subjects commented on the ease of maintaining the ventilatory target when the PETc02 was 50 mm Hg. One subject
-----
CONDITION B
CONDITION A
Fig. 1. Mean breathlessness ratings for each subject and for the group as a whole (expressed as centimeters of VAS).In Condition A, PETc0 2 was maintained at 40 mm Hg and in Condition B PETC0 2 was increased to 50 mm Hg. Each subject is denoted by a different symbol. The mean increase in breathlessness ratings was significantly greater for Condition B than for Condition A (p < 0.05).
40
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Fig. 2. Mean effort ratings foreach subject and for the group as a whole (expressed as centimeters of VAS).In Condition A, PET CO 2 was maintained at 40 mm Hg, and in Condition B, PETC02 was increased to 50 mm Hg. Same symbols as in figure 1. The mean change in effort ratings between the two conditions was significant (p < 0.05).
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1224
DEMEDIUK, MANNING, LILLY, ET AL.
mean inspiratory flow were not significantly different during the two experiOPD mental conditions. Thus, muscle tension 20 20 • BF Z should have been similar under these two "i=« o DG conditions. While we cannot absolutely • TK 10 • x a: 10 .. KM ~ exclude the possibility that our subjects ..I x i i x .. FR w A rated tension rather than effort, this o • APO "«J:Z X • would .WA not explain the significant differ0 XMEAN -10 -10 ence in effort ratings between conditions in which respiratory muscle tension was -20 -20 likely very similar. For both breathlessBREATHLESSNESS EFFORT EFFORT BREATHLESSNeSS ness and effort ratings, we used a visual Fig. 3. Mean change in effort and breathlessness ratings for each subject for Conditions A and B. Same symbols analog scale (VAS), a scaling method that as figure 1. has been widely used in studies of respiratory sensation (8,9, 12, 13). Although we did not discuss the possible relationTABLE 1 ship between effort and breathlessness RESPIRATORY VARIABLES with the subject, we may have unintenCondition B Condition A tionally suggested that we expected the Test Test Control Control ratings to differ by asking for separate p Value (PETC02 = 40) (PETC02 = 50) (PETC02 = 40) (PETC02 = 40) ratings for the two sensations. This, however, would not account for the finding 56.0 ± 7.6 58.7 ± 8.7 56.9 ± 8.3 VE, Llmin 56.9 ± 7.3 NS 1.4 ± 0.5 1.3 ± 0.3 VT, L 1.3 ± 0.4 1.2 ± 0.5 of a dissociation between effort and NS f, mln' 49.9 ± 23.6 59.3 ± 39.7 47.4 ± 18.8 50.5 ± 30.6 NS breathlessness during hypercapnia, while 0.5 ± 0.1 TllTtot 0.4 ± 0.1 0.4 ± 0.1 0.4 ± 0.1 NS effort and breathlessness both increased VTITI, LIs 2.44 ± 0.5 2.4 ± 0.5 NS 2.2 ± 0.4 2.3 ± 0.4 during eucapnia. Although our subjects % rib cage 68 ± 14 65 ± 10 NS 69 ± 13 69 ± 15 felt they could assess effort and breathFRC, L 0.4 ± 0.4 0.0 ± 0.2 0.3 ± 0.2 0.3 ± 0.4 P < 0.5 lessness independently, we cannot absoDefinitionof abbreviations: Ve = minute ventllat'on: Vr = tidal volume; f = respiratory frequency; TIlTtot = duty cycle; VrlTl = mean inspiratory flow; % rib cage = relative contribution of rib cage compartment to total ventilation; FRC = change in func- lutely exclude the possibility that the sentional residual capacity. sations associated with hypercapnia had an impact on the intensity rating for the sense of effort. The discomfort accomvolunteered that he had difficulty trying niques used may influence the results ob- panying the trials with hypercapnia may not to exceed the target ventilation dur- tained. Thus, in comparing our results have distracted the subject so as to dimining hypercapnic stimulation. All subjects with those of other investigators who ish the rating of effort. However, in Connoted increased dyspnea with the have found a close concordance between dition A (PC02 maintained at 40 mm Hg), effort and breathlessness (1, 4, 11), one several subjects had an increase in both hypercapnia. must ask whether the apparently conflict- effort and breathlessness during the test Discussion ing findings of our study can be explained period. This would suggest that breathThe aim of our study was to explore the simply on the basis of differences in lessness, per se, does not result in a derelationship between the sensations of methodology. Our definition of breath- crease in effort by virtue of distraction. breathlessness and respiratory effort lessness was similar to that used by other In sum, we believe it very unlikely that while inducing reflex and voluntary in- investigators in defining the breathless- the findings of our study can be explained creases in ventilation. With a compara- ness associated with hypercapnia (8). solely on the basis of differences in defible level of ventilation and pattern of Most previous studies of respiratory mus- nitions or scaling techniques. breathing, reflex stimulation of venti- cle effort have not stated whether or how Some controversy exists as to whether lation with CO 2 induced significantly effort was defined in the instructions giv- the sense of effort arises from activity greater breathlessness than voluntary en to the subjects. Weinstructed subjects in the motor cortex or is dependent on hyperpnea. This confirms the work of to rate effort using the simple analogy stimulation of peripheral receptors, e.g., several other investigators (8-10). How- of the sensation that accompanies the in ventilatory muscles (14). Some invesever, in contrast to studies that have used lifting of a weight (as opposed to the sen- tigators believe that the sense of effort respiratory loads to induce breathlessness sation associated with the muscular con- arises from corollary discharges transmit(4), we found that with hypercapnia as traction elicited by tapping a tendon). ted from a motor center to a sensory cena respiratory stimulus and with the level Our analogy was intended to illustrate ter at the same time as the outgoing moof ventilation held constant, the sense of for the subjects the difference between tor command is sent to the ventilatory effort was inversely correlated with re- effort and tension: lifting a weight in- muscles (15-18). For the limb muscles, flexinduced changes in ventilation. Thus, volves both effort and tension, whereas this corollary discharge must arise in the we demonstrated that breathlessness per- the tendon reflex results in muscle ten- motor cortex. However,because there are ceived during hypercapnia was dissociat- sion, but the effort is nil. Thus, our defi- two sources of control for the respiratoed from the sensation of respiratory nition should not have caused subjects ry muscles, the automatic or reflex syseffort. to rate other sensations, such as muscle tem in the brain stem and the voluntary In any study involving subjective sen- tension, in preferenceto effort. Moreover, system in the motor cortex (19), the corolsations, the definitions and scaling tech- the ventilation, pattern of breathing, and lary discharge could, in theory, arise in CONDITION A
CONDITION B
30
30
C
.
1225
DISSOCIATION BETWEEN DYSPNEA AND RESPIRATORY EFFORT
either of these sites. We reasoned that if both total ventilation and pattern of ventilation wereconstant, total neuromotor output to the respiratory muscles would also be constant, but that depending upon the PETc02' the relative contributions of the brain stem and cortex to total neuromotor output would vary. Because we had subjects target their ventilation to a level above that dictated by chemical drive, there was at least some volitional element, i.e., cortical control, to ventilation even during the hypercapnic trial periods. Under these circumstances of constant ventilation, feedback from peripheral receptors should have been constant as well;thus, any variation in sense of effort would imply a central rather than peripheral mechanism. We found that as PETC02 increased, a condition in which reflex hyperpnea would be presumed to contribute more significantly to total ventilation (with a resultant decrease in the volitional component of the hyperpnea), the senseof effort decreased. This suggests that the sense of effort involves central rather than peripheral mechanisms, and that there is less corollary discharge associated with reflex hyperpnea than volitional hyperpnea. Although reflex hyperpnea resulting from stimulation of the chemoreceptors does not appear to produce as great a sense of effort as voluntary hyperpnea, there is substantial evidence that the chemoreceptors make an important and independent contribution to breathlessness (8-10, 12). Thus, the dissociation between effort and breathlessness observed in our study may result from the fact that during hypercapnia, different neural mechanisms underlie each of the sensations. Breathlessness may have increased during hypercapnia as a result of increased brain stem activity or as a result of direct projections from the chemoreceptor to the sensory cortex. Effort, on the other hand, may have decreased with hypercapnia as the origin of the outgoing motor command to the respiratory muscles shifted from the cortex to the brain stem, and the resulting corollary discharge diminished. Wecannot exclude the possibility that mechanical factors contributed to the inverse relationship between effort ratings
and chemical drive. A number of mechanical factors have been shown to alter the sense of respiratory effort (4). Although we targeted the subjects to a constant level of total ventilation, we were unable to control completely their pattern of breathing. In pilot studies, subjects were unable to successfully copy a displayed pattern of ventilation. Despite this, our data demonstrate that not only were subjects successful in targeting total ventilation, but they also achieved remarkably similar patterns of breathing during the eucapnic and hypercapnic periods (table 1). There was a small but significant decrease in FRC during the hypercapnic trials, consistent with recruitment of expiratory muscles during hypercapnia. Killian and colleagues (1) demonstrated that when the inspiratory muscles wereshortened and weakened by a mean increase in lung volume of 1.1 Labove FRC, effort increased. Although in our study, the mean difference in FRC between the eucapnic and hypercapnic test periods (0.4 L) was much smaller than in the study of Killian and coworkers, it is possible that during the hypercapnic periods, the greater end-expiratory length and accompanying mechanical advantage of the inspiratory muscles may have contributed to the decreased sense of effort. In summary, our finding of a dissociation between effort and breathlessness during hypercapnia suggests that these sensations are neither identical nor mediated by the same mechanism. Rather, effort may be one of a number of factors that contributes to the sensation of breathlessness, and although it may well be the predominant factor contributing to breathlessness when the respiratory muscles are fatigued, weakened, or faced with an increased load, effort may play a lessimportant role in other settings. Additionally, our findings of an inverserelationship between effort and chemical drive suggest that the sense of effort arises predominantly from cortical rather than brain stem respiratory motor activity. References 1. Killian KJ, Gandevia SC, Summers E, Campbell ElM. Effect of increased lung volume on per-
ception of breathlessness, effort, and tension. J Appl Physiol 1984; 57:686-91. 2. Gandevia SC, Killian KJ, Campbell ElM. The effect of respiratory muscle fatigue on respiratory sensations. Clin Sci 1981; 60:463-6. 3. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822-8. 4. EI-Manshawi A, Killian KJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986; 61:896-905. 5. Schwartzstein RM, Simon PM, WeissJW, Fencl V, Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231-7. 6. Leith DE. Target device for regulating ventilation during voluntary hyperpnea. J Appl Physiol 1983; 55:1932-5. 7. Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol 1967; 22:407-22. 8. Adams L, Lane R, Shea SR, Cockcroft A, Guz A. Breathlessness during different forms of ventilatory stimulation: a study in normal subjects and respiratory patients. Clin Sci 1985; 69:663-72. 9. Chonan T, Mulholland MB, Leitner J, Altose MD, Cherniack NS. Sensation of dyspnea during hypercapnia, exercise and voluntary hyperventilation. J Appl Physiol 1990; 69:2100-6. 10. Stark RD, Gambles SA, Lewis JA. Methods to assess breathlessness in healthy subjects. Clin Sci 1981; 61:429-39. 11. Freedman S, Lane R, Guz A. Breathlessness and respiratory mechanics during reflex or voluntary hyperventilation in patients with chronic airflow limitation. Clin Sci 1987; 73:311-8. 12. Killian KJ, Bucens DD, Campbell EJM. Effect of breathing patterns on the perceived magnitude of added loads to breathing. J Appl Physiol 1982; 52:578-84. 13. Adams L, Chronos N, Lane R, Guz A. The measurement of breathlessness induced in normal subjects: validity of two scaling techniques. Clin Sci 1985; 69:7-16. 14. Altose MD, Dimarco AF, Gottfried SB, Strohl KP. The sensation of respiratory muscle force. Am Rev Respir Dis 1982; 126:807-11. 15. Gandevia SC, McCloskey DI. Sensation of heaviness. Brain 1977; 100:345-54. 16. Gandevia SC, McCloskey DI. Changes in motor commands, as shown by changes in perceived heaviness, during partial curarization and peripheral muscle anesthesia in man. J Physiol (Lond) 1977; 272:673-89. 17. Matthews PBC. Where does Sherrington's "muscular sense" originate? Muscles, joints, corollary discharges? Annu Rev Neurosci 1982; 5:189-218. 18. McCloskey OJ, Ebeling P, Goodwin GM. Estimation of weights and tensions and apparent involvement of a "sense of effort." Exp Neuro11974; 42:220-32. 19. Mitchell RA, Berger AI. Neural regulation of respiration. Am Rev Respir Dis 1975; 111:206-24.
BARBARA H. DEMEDIUK, HAROLD MANNING, JENNIFER LILLY, VLADIMIR FENCL, STEVEN E. WEINBERGER, J. WOODROW WEISS, and RICHARD M. SCHWARTZSTEIN
Introduction
Studies of voluntary muscles suggest that the sense of muscular effort arises from perception of the outgoing command from the motor cortex (1-3). For the respiratory muscles, this sense of muscular effort may contribute to the sensation of breathlessness.El-Manshawi and colleagues (4) studied normal subjects during exercise and found that breathlessness was related to several indices of respiratory muscle effort. They concluded that the sense of effort was "ideally suited to mediate the sensation of breathlessness." Killian and coworkers (1) demonstrated that perceived breathlessness and perceived effort closely paralleled one another during breathing with a range of elastic loads, and when the inspiratory muscles wereweakened by an increase in lung volume. Indeed, on the basis of these findings, Killian and colleagues concluded that "breathlessness and effort are identical and mediated by the same mechanism." However, under some circumstances, both clinical and experimental, the relationship between breathlessness and effort is less apparent. In our experience, patients with pulmonary embolism or pulmonary hypertension may report breathlessness that appears to be out of proportion to factors normally associated with respiratory effort, e.g., minute ventilation and changes in pulmonary mechanics. Individuals with severe lung disease may report breathlessness when attempting to suppress ventilation briefly while eating or speaking. Similarly, when normal subjects suppress their ventilation to a level below that dictated by chemical drive, breathlessness increases without corresponding increases in indices of respiratory muscle effort (5). Because of these apparent discrepancies, we sought to examine further the relationship between breathlessness and respiratory effort. Moreover, because the respiratory musclesare unique among the skeletal muscles in having both cortical and brain stem control, we hypothesized 1222
SUMMARY Breathlessness induced by hypercapnia may be related to the sensation of respiratory effort or to the central or peripheral effects of CO2 , To examine the relationship among breathlessness, respiratory effort, and hypercapnia, we studied eight normal naive subjects. By using a visual feedback system, subjects maintained a constant ventilation of 50-60 Umin. PETC0 2 was held at 40 mm Hg during the first 2 min of each trial (control period), then for 4 min (test period) was either kept at 40 mm Hg or elevated to 50 mm Hg. At the end of each control and test period, subjects were asked to give separate ratings for dyspnea (an unpleasant urge to breathe) and for the sense of respiratory effort (analogous to lifting a weight) on a 50-cm visual analog scale. Hypercapnia was associated with a significant reduction In effort ratings (-7.3 ± 6.4, mean ± SO, P < 0.05) and a concomitant Increase In dyspnea ( +6.6 ± 6.0, P < 0.05). Weconclude that dyspnea associated with hypercapnia Is dissociated from changes In respiratory effort, and that CO2 has a direct central effect that leads to breathlessness. Our data also suggest that the sense of effort at a given level of ventilation Is less when the ventilation is the result of "reflex" stimuli to breathe rather than "volunAM REV RESPIR DIS 1992; 146:1222-1225 tary" signals to the respiratory muscles.
that the sense of respiratory muscle effort would vary with the origin of the respiratory motor command. Methods
Subjects Westudied five male and three female volunteers aged 27 to 34 years. Subjects were excluded if they had a history of cardiac or pulmonary disease, migraine headaches, or seizures. All of the subjects were naive to the purpose of the study. The protocol was approved by the Committee on ClinicalInvestigation at Beth IsraelHospital, and informed consent was obtained from all subjects in accordance with the guidelines of this committee.
Techniques Breathingcircuit. Each subject was seated in a straight-back chair that allowed position to be fixed. The subjects wore noseclips and breathed through an Otis-McKerrow valve connected to a Fleish pneumotachograph (no. 3). The inspiratory limb of the circuit was attached to a differential manometer calibrated to ventilation (6). The visual display from this device was used to target ventilation. Measurement ofrespiratory variables. Inspiratory flow was measured with the pneumotachograph, and inspired tidal volume (VT) was obtained by electrical integration of the flow signal (Hewlett Packard 8815A;Hewlett Packard, Waltham, MA). Inspiratory time (TI), total respiratory cycle time (not), and frequency (f) were measured from the flow tracing. Pairs of magnetometer coils were
placed anteroposteriorly on the rib cage at the levelof the midsternum and on the abdomen just above the umbilicus.The magnetometers were calibrated by the isovolume method (7). The relative contribution of the rib cage compartment to total ventilation was obtained by dividing the amplitude of the rib cage signal by the sum of the rib cage and abdominal signals. In order to determine changes in functional residualcapacity (PRC), the signals from the magnetometer coils were summed and then converted to an absolute volume by calibration with the volume obtained from integration of the flow signal. End-tidal CO 2(PETC02) was measured at the mouth with a mass spectrometer (Perkin Elmer 1100; Perkin-Elmer, Pomona, CA). All signals were continuously recorded on a strip chart recorder (Hewlett Packard 7758B) for subsequent analysis.
(Received in original form May 8, 1991 and in revised form March 6, 1992) 1 From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. 2 Supported by the Pulmonary SCOR grant HL-19170. 3 Presented in part at the Annual Meeting of the American Thoracic Society, Boston, Massachusetts, May 1990. 4 Correspondence and requests for reprints should be addressed to Richard M. Schwartzstein, M.D., Pulmonary Unit, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215.
1223
DISSOCIATION BETWEEN DYSPNEA AND RESPIRATORY EFFORT
Assessment of ventilatory responsiveness to CO2 • Subjects breathed air while 100% CO2 was added to the inspiratory limb of the circuit at a rate sufficient to maintain PETC 02 constant at 55 mm Hg for 5 min. Because we wanted to target subjects to a levelof ventilation that would require at least a moderate levelof respiratory effort (seelater, under Protocol), we excluded from the study subjects whose ventilation at the end of the 5-min period was less than 250/0 oftheir predicted maximal voluntary ventilation. Quantitation of breathlessness and respiratory effort. Each subject was given written instructions to read. The subjects were told that the inspired concentrations of carbon dioxide and/or oxygen might vary, and that at various intervals they would be asked to rate their respiratory sensations. Breathlessness was defined as an "unpleasant urge to breathe." Effort was described as a sensation analogous to the one that accompanies the volitional act oflifting a weight (as compared with the sensation associated with the muscular contraction elicited by tapping a tendon). At the end of each test period, subjects were asked to rate these sensations using a visual analog scale that consisted of a 50-cm bar with a sliding disk attached. The markings on the scale were visible only to the investigators. The left end of the scale was defined as no effort or breathlessness, and the right end was defined as maximal effort or breathlessness. The subject was told to move the disk a distance proportional to the intensity of the sensation, and for each rating period, the distance of the disk from the origin (in centimeters) was recorded and taken as the subject's rating for that period. Protocol The subjects' PETc02 was maintained at 55 mm Hg for 5 min, and their ventilation during the final minute was recorded. After a 5-min rest, the subjects wereinstructed to target their ventilation to a level 5 to 10 L/min greater than that achieved spontaneously at the end of the 5 min at PETc02 = 55 mm Hg. We chose this higher level of ventilation to eliminate any need for the subjects to suppress their ventilation during the subsequent repeated periods of hypercapnia. Each trial lasted 6 min and consisted of an initial 2-min control period followed by a 4-min test period. The subjects maintained their ventilation at the assigned target throughout the entire trial. For each control period, PETC02 was held constant at 40 mm Hg, and during the final 30 s, the subjects were asked to provide separate ratings first for effort and then for breathlessness. The VAS was reset to zero between ratings. During the test period, PETC02 was either maintained at 40 mm Hg (Condition A) or increased to 50 mm Hg (Condition B). During the final 30 s of the test period, the subjects were shown first their effort and then their breathlessness ratings from the control period and asked to give a second set of ratings. There werea total of sixtrials, three using
Condition A and three using Condition B, scheduled at random. There was a to-min rest period between the trials, all of which were conducted at one sitting. At the conclusion of each trial the subjects were asked to comment on their sensations during the study.
(19.6 ± 5.7 em for Condition A versus 18.6 ± 6.0 em for Condition B). However, when PETc02 was maintained at 40 mm Hg for the test period (Condition A), effort ratings increased, whereas when PETC02 was increased to 50 mm Hg during the test period (Condition B), effort ratings decreased (mean change in effort ratings 3.3 ± 6.8 versus -4.0 ± 5.4, respectively, p < 0.05). The range in ratings for effort was 0 to 37. Figure 3 demonstrates the relative changes in effort and breathlessness ratings for Condition A and B. When PETc02 was maintained at 40 mm Hg during the test period (Condition A), both effort and breathlessness ratings increased. In contrast, when PETCO 2 was increased to 50 mm Hg during the test period (Condition B), effort ratings decreased while breathlessness ratings increased.
Data Analysis For each trial we calculated the differences between the control and rest periods for the breathlessness and effort ratings and the various respiratory variables. The differences between Conditions A and B were then compared using a two-tailed paired ttest. A p value of < 0.05 was considered significant. Data are expressed as mean ± So. Results
Breathlessness Ratings The mean ratings for each subject under the control and test conditions as well as the mean ratings for the group as a whole are shown in figure 1. There was no significant difference in mean breathlessness ratings between the two control periods (9.8 ± 10.5 em for Condition A versus 9.3 ± 8.8 em for Condition B). Although breathlessness ratings increased from the control to the test period in both Conditions A and B, the mean increase in breathlessness rating was significantly greater for Condition B (9.4± 7.2 versus 3.0 ± 6.0, p < 0.05). The range in ratings for breathlessness was 0 to 45.
Effort Ratings The mean ratings for each subject under the control and test conditions as well as the mean ratings for the group as a whole are shown in figure 2. There was no significant difference between the two control periods in mean effort ratings
Respiratory Variables (table 1) The respiratory variables minute ventilation, tidal volume, frequency, mean inspiratory flow, duty cycle, and the relative contribution of the rib cage compartment to total ventilation did not vary significantly throughout the experimental protocol. There was a small but statistically significant difference in the change in FRC between Condition A and Condition B (p < 0.05), i.e., there was a greater decrease in FRC during Condition B.
Subjective Comments Two subjects commented on the ease of maintaining the ventilatory target when the PETc02 was 50 mm Hg. One subject
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Fig. 1. Mean breathlessness ratings for each subject and for the group as a whole (expressed as centimeters of VAS).In Condition A, PETc0 2 was maintained at 40 mm Hg and in Condition B PETC0 2 was increased to 50 mm Hg. Each subject is denoted by a different symbol. The mean increase in breathlessness ratings was significantly greater for Condition B than for Condition A (p < 0.05).
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1224
DEMEDIUK, MANNING, LILLY, ET AL.
mean inspiratory flow were not significantly different during the two experiOPD mental conditions. Thus, muscle tension 20 20 • BF Z should have been similar under these two "i=« o DG conditions. While we cannot absolutely • TK 10 • x a: 10 .. KM ~ exclude the possibility that our subjects ..I x i i x .. FR w A rated tension rather than effort, this o • APO "«J:Z X • would .WA not explain the significant differ0 XMEAN -10 -10 ence in effort ratings between conditions in which respiratory muscle tension was -20 -20 likely very similar. For both breathlessBREATHLESSNESS EFFORT EFFORT BREATHLESSNeSS ness and effort ratings, we used a visual Fig. 3. Mean change in effort and breathlessness ratings for each subject for Conditions A and B. Same symbols analog scale (VAS), a scaling method that as figure 1. has been widely used in studies of respiratory sensation (8,9, 12, 13). Although we did not discuss the possible relationTABLE 1 ship between effort and breathlessness RESPIRATORY VARIABLES with the subject, we may have unintenCondition B Condition A tionally suggested that we expected the Test Test Control Control ratings to differ by asking for separate p Value (PETC02 = 40) (PETC02 = 50) (PETC02 = 40) (PETC02 = 40) ratings for the two sensations. This, however, would not account for the finding 56.0 ± 7.6 58.7 ± 8.7 56.9 ± 8.3 VE, Llmin 56.9 ± 7.3 NS 1.4 ± 0.5 1.3 ± 0.3 VT, L 1.3 ± 0.4 1.2 ± 0.5 of a dissociation between effort and NS f, mln' 49.9 ± 23.6 59.3 ± 39.7 47.4 ± 18.8 50.5 ± 30.6 NS breathlessness during hypercapnia, while 0.5 ± 0.1 TllTtot 0.4 ± 0.1 0.4 ± 0.1 0.4 ± 0.1 NS effort and breathlessness both increased VTITI, LIs 2.44 ± 0.5 2.4 ± 0.5 NS 2.2 ± 0.4 2.3 ± 0.4 during eucapnia. Although our subjects % rib cage 68 ± 14 65 ± 10 NS 69 ± 13 69 ± 15 felt they could assess effort and breathFRC, L 0.4 ± 0.4 0.0 ± 0.2 0.3 ± 0.2 0.3 ± 0.4 P < 0.5 lessness independently, we cannot absoDefinitionof abbreviations: Ve = minute ventllat'on: Vr = tidal volume; f = respiratory frequency; TIlTtot = duty cycle; VrlTl = mean inspiratory flow; % rib cage = relative contribution of rib cage compartment to total ventilation; FRC = change in func- lutely exclude the possibility that the sentional residual capacity. sations associated with hypercapnia had an impact on the intensity rating for the sense of effort. The discomfort accomvolunteered that he had difficulty trying niques used may influence the results ob- panying the trials with hypercapnia may not to exceed the target ventilation dur- tained. Thus, in comparing our results have distracted the subject so as to dimining hypercapnic stimulation. All subjects with those of other investigators who ish the rating of effort. However, in Connoted increased dyspnea with the have found a close concordance between dition A (PC02 maintained at 40 mm Hg), effort and breathlessness (1, 4, 11), one several subjects had an increase in both hypercapnia. must ask whether the apparently conflict- effort and breathlessness during the test Discussion ing findings of our study can be explained period. This would suggest that breathThe aim of our study was to explore the simply on the basis of differences in lessness, per se, does not result in a derelationship between the sensations of methodology. Our definition of breath- crease in effort by virtue of distraction. breathlessness and respiratory effort lessness was similar to that used by other In sum, we believe it very unlikely that while inducing reflex and voluntary in- investigators in defining the breathless- the findings of our study can be explained creases in ventilation. With a compara- ness associated with hypercapnia (8). solely on the basis of differences in defible level of ventilation and pattern of Most previous studies of respiratory mus- nitions or scaling techniques. breathing, reflex stimulation of venti- cle effort have not stated whether or how Some controversy exists as to whether lation with CO 2 induced significantly effort was defined in the instructions giv- the sense of effort arises from activity greater breathlessness than voluntary en to the subjects. Weinstructed subjects in the motor cortex or is dependent on hyperpnea. This confirms the work of to rate effort using the simple analogy stimulation of peripheral receptors, e.g., several other investigators (8-10). How- of the sensation that accompanies the in ventilatory muscles (14). Some invesever, in contrast to studies that have used lifting of a weight (as opposed to the sen- tigators believe that the sense of effort respiratory loads to induce breathlessness sation associated with the muscular con- arises from corollary discharges transmit(4), we found that with hypercapnia as traction elicited by tapping a tendon). ted from a motor center to a sensory cena respiratory stimulus and with the level Our analogy was intended to illustrate ter at the same time as the outgoing moof ventilation held constant, the sense of for the subjects the difference between tor command is sent to the ventilatory effort was inversely correlated with re- effort and tension: lifting a weight in- muscles (15-18). For the limb muscles, flexinduced changes in ventilation. Thus, volves both effort and tension, whereas this corollary discharge must arise in the we demonstrated that breathlessness per- the tendon reflex results in muscle ten- motor cortex. However,because there are ceived during hypercapnia was dissociat- sion, but the effort is nil. Thus, our defi- two sources of control for the respiratoed from the sensation of respiratory nition should not have caused subjects ry muscles, the automatic or reflex syseffort. to rate other sensations, such as muscle tem in the brain stem and the voluntary In any study involving subjective sen- tension, in preferenceto effort. Moreover, system in the motor cortex (19), the corolsations, the definitions and scaling tech- the ventilation, pattern of breathing, and lary discharge could, in theory, arise in CONDITION A
CONDITION B
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1225
DISSOCIATION BETWEEN DYSPNEA AND RESPIRATORY EFFORT
either of these sites. We reasoned that if both total ventilation and pattern of ventilation wereconstant, total neuromotor output to the respiratory muscles would also be constant, but that depending upon the PETc02' the relative contributions of the brain stem and cortex to total neuromotor output would vary. Because we had subjects target their ventilation to a level above that dictated by chemical drive, there was at least some volitional element, i.e., cortical control, to ventilation even during the hypercapnic trial periods. Under these circumstances of constant ventilation, feedback from peripheral receptors should have been constant as well;thus, any variation in sense of effort would imply a central rather than peripheral mechanism. We found that as PETC02 increased, a condition in which reflex hyperpnea would be presumed to contribute more significantly to total ventilation (with a resultant decrease in the volitional component of the hyperpnea), the senseof effort decreased. This suggests that the sense of effort involves central rather than peripheral mechanisms, and that there is less corollary discharge associated with reflex hyperpnea than volitional hyperpnea. Although reflex hyperpnea resulting from stimulation of the chemoreceptors does not appear to produce as great a sense of effort as voluntary hyperpnea, there is substantial evidence that the chemoreceptors make an important and independent contribution to breathlessness (8-10, 12). Thus, the dissociation between effort and breathlessness observed in our study may result from the fact that during hypercapnia, different neural mechanisms underlie each of the sensations. Breathlessness may have increased during hypercapnia as a result of increased brain stem activity or as a result of direct projections from the chemoreceptor to the sensory cortex. Effort, on the other hand, may have decreased with hypercapnia as the origin of the outgoing motor command to the respiratory muscles shifted from the cortex to the brain stem, and the resulting corollary discharge diminished. Wecannot exclude the possibility that mechanical factors contributed to the inverse relationship between effort ratings
and chemical drive. A number of mechanical factors have been shown to alter the sense of respiratory effort (4). Although we targeted the subjects to a constant level of total ventilation, we were unable to control completely their pattern of breathing. In pilot studies, subjects were unable to successfully copy a displayed pattern of ventilation. Despite this, our data demonstrate that not only were subjects successful in targeting total ventilation, but they also achieved remarkably similar patterns of breathing during the eucapnic and hypercapnic periods (table 1). There was a small but significant decrease in FRC during the hypercapnic trials, consistent with recruitment of expiratory muscles during hypercapnia. Killian and colleagues (1) demonstrated that when the inspiratory muscles wereshortened and weakened by a mean increase in lung volume of 1.1 Labove FRC, effort increased. Although in our study, the mean difference in FRC between the eucapnic and hypercapnic test periods (0.4 L) was much smaller than in the study of Killian and coworkers, it is possible that during the hypercapnic periods, the greater end-expiratory length and accompanying mechanical advantage of the inspiratory muscles may have contributed to the decreased sense of effort. In summary, our finding of a dissociation between effort and breathlessness during hypercapnia suggests that these sensations are neither identical nor mediated by the same mechanism. Rather, effort may be one of a number of factors that contributes to the sensation of breathlessness, and although it may well be the predominant factor contributing to breathlessness when the respiratory muscles are fatigued, weakened, or faced with an increased load, effort may play a lessimportant role in other settings. Additionally, our findings of an inverserelationship between effort and chemical drive suggest that the sense of effort arises predominantly from cortical rather than brain stem respiratory motor activity. References 1. Killian KJ, Gandevia SC, Summers E, Campbell ElM. Effect of increased lung volume on per-
ception of breathlessness, effort, and tension. J Appl Physiol 1984; 57:686-91. 2. Gandevia SC, Killian KJ, Campbell ElM. The effect of respiratory muscle fatigue on respiratory sensations. Clin Sci 1981; 60:463-6. 3. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822-8. 4. EI-Manshawi A, Killian KJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986; 61:896-905. 5. Schwartzstein RM, Simon PM, WeissJW, Fencl V, Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231-7. 6. Leith DE. Target device for regulating ventilation during voluntary hyperpnea. J Appl Physiol 1983; 55:1932-5. 7. Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol 1967; 22:407-22. 8. Adams L, Lane R, Shea SR, Cockcroft A, Guz A. Breathlessness during different forms of ventilatory stimulation: a study in normal subjects and respiratory patients. Clin Sci 1985; 69:663-72. 9. Chonan T, Mulholland MB, Leitner J, Altose MD, Cherniack NS. Sensation of dyspnea during hypercapnia, exercise and voluntary hyperventilation. J Appl Physiol 1990; 69:2100-6. 10. Stark RD, Gambles SA, Lewis JA. Methods to assess breathlessness in healthy subjects. Clin Sci 1981; 61:429-39. 11. Freedman S, Lane R, Guz A. Breathlessness and respiratory mechanics during reflex or voluntary hyperventilation in patients with chronic airflow limitation. Clin Sci 1987; 73:311-8. 12. Killian KJ, Bucens DD, Campbell EJM. Effect of breathing patterns on the perceived magnitude of added loads to breathing. J Appl Physiol 1982; 52:578-84. 13. Adams L, Chronos N, Lane R, Guz A. The measurement of breathlessness induced in normal subjects: validity of two scaling techniques. Clin Sci 1985; 69:7-16. 14. Altose MD, Dimarco AF, Gottfried SB, Strohl KP. The sensation of respiratory muscle force. Am Rev Respir Dis 1982; 126:807-11. 15. Gandevia SC, McCloskey DI. Sensation of heaviness. Brain 1977; 100:345-54. 16. Gandevia SC, McCloskey DI. Changes in motor commands, as shown by changes in perceived heaviness, during partial curarization and peripheral muscle anesthesia in man. J Physiol (Lond) 1977; 272:673-89. 17. Matthews PBC. Where does Sherrington's "muscular sense" originate? Muscles, joints, corollary discharges? Annu Rev Neurosci 1982; 5:189-218. 18. McCloskey OJ, Ebeling P, Goodwin GM. Estimation of weights and tensions and apparent involvement of a "sense of effort." Exp Neuro11974; 42:220-32. 19. Mitchell RA, Berger AI. Neural regulation of respiration. Am Rev Respir Dis 1975; 111:206-24.
