Oral Mucosal Stimulation Modulates Intensity of Breathlessness Induced in Normal Subjects 1- 4
PEGGY M. SIMON, ROBERT C. BASNER, STEVEN E. WEINBERGER, VLADIMIR FENCL,
J. WOODROW WEISS, and RICHARD M. SCHWARTZSTEIN
Introduction
Patients with chronic obstructive lung disease (COPD) have often been observed to complain of severe dyspnea when a mouthpiece is used in the performance of pulmonary function tests. When normal subjects breathe through a mouthpiece, their respiratory neuromuscular output is generally increased, as evidenced by increases in minute ventilation (VE), tidal volume (VT), and mean inspiratory flow (VT/TI) (1-3). The respiratory pattern also changes (1, 3). Western and Patrick suggested that awareness of breathing could account for the changes in inspiratory pattern observed when a mask is applied to the face (4). However, other studies indicate that the shift from nasal to oral or oronasal respiration with a mouthpiece stimulates receptors in the nose, mouth, and pharynx, leading to changes in ventilation and breathing pattern (5, 6). The flow of cold air through the nose has been associated with a reduction in the ventilatory response to hypercapnia (7, 8) and prolongation of breath-holding time (9). From these findings, one might conclude that the dyspnea perceived by patients with COPD when breathing through a mouthpiece is provoked by an increased neuromuscular output. An alternative to this hypothesis is that the increased dyspnea associated with the mouthpiece is due to changes in afferent information from oral receptors. A study in normal subjects (10) showed that the flow of cold air on the face reduces breathlessness associated with hypercapnia and inspiratory resistive loading (presumably stimulating receptors that, like the buccal mucosa, are innervated by the trigeminal nerve). The purpose of our study was to determine whether stimulation of receptors in the oral mucosa decreases the sensation of breathlessness independently of changes in ventilation and pattern of breathing. We hypothesized that breathing through a mouthpiece would bypass
SUMMARY Patients with chronic obstructive pUlmonary disease (COPO)often report an Increase In breathle..ness when they breathe through a mouthpiece. We hypoth.slzed that stimulation of receptors In the oral mucosa modulat.s the sensation of breathl...n.... W. studied 10 normal naive volunteers In whom breathl ...ne.. was Induced by having th.m breath. for 4 min with an Inspiratory resistive load (18 em H 20/Us) while breathing was stimulated by CO2 Inhalation (.ndtidal PC0 2 maintained at 55 mm Hg). Initially, subjects breath.d with a tight-fitting face mask and Inspiratory flow was displayed on a storage oscilloscope. In subsequent trials, the subjects were asked to match this trace, which controlled ventilation and the pattern of breathing. Subjects performed eight trials, four with the tight-fitting mask only (M) and four with a mouthpiece and the mask (MM). M and MM were alternated; the Initial condition was chosen at random. following each of the trials, subjects rated the Intensity of their breathle..ne.. by choosing a number from a modified Borg scale. On the average, subjects were more breathless while breathing with the mask and mouthpiece than with ttie mask alone (mean ratings of breathle..ne.. 6.6 ± 1.1 and 5.6 ± 1.8 units, p < 0.01). Six subjects repeated the protocol on 2 additional days: 1 dllY with Inhalation of warm (340 C), humidified air and 1 dllY after toplcel application of 4% lidocaine to the oral mucosa. Both these Interventions abolished the differences In breathl...n... between mask and mouthpiece and mask alone. Weconclude that afferent Information from oral mucosal stimulation Influences AM REV RESPIR DIS 1991; 144:419-422 the Intensity of breathlessne...
these "flow receptors," resulting in an in- tee on Clinical Investigations at the Beth Israel Hospital. crease in breathlessness. Reducing the stimulation of these flow receptors by Protocol anesthesia or warm, humidified air would ' Nine trials were performed during each of the have a similar effect on breathlessness. three study sessions. During each trial subTo test this hypothesis, we studied in nor- jects inspired for 4 min through a resistive mal subjects the effect of breathing load (18 em H 20/L/s, between 0.5 and 1.5 through a mask (M) or through a mask Lis, created with sintered filters) while CO 2 and mouthpiece (MM) on the breathless- was added to the inspired gas to maintain the ness produced by hypercapnia combined end-tidal partial pressure of carbon dioxide with an inspiratory resistive load. Simi- (PETeo2) at 55 mm Hg. End-tidal Pco, was monitored with a mass larly, breathlessness ratings were compared between the two breathing conditions (M and MM) after oral mucosal anesthesia and inhalation of warm, hu- (Received in original form November ~ 1989 and midified air on 2 separate days. Minute in revised form January 2, 1991) ventilation and respiratory pattern were From the Charles A. Dana Research Institute controlled to eliminate changes in neuand the Harvard-Thorndike Laboratory, Beth isromuscular output as an explanation for rael Hospital; the Department of Medicine, Beth differences in breathlessness between Israel Hospital and Harvard Medical School, Bosbreathing with a mask or a mask and ton, Massachusetts; and the Department of Medicine, Wm. S. Middleton Memorial VAHospital and mouthpiece. 1
Methods Subjects A group of 10 naive normal volunteers were recruited from local colleges. The ages of the subjects ranged from 18 to 33 yr. No subject had a history of pulmonary or cardiac disease. Informed consent was obtained in accordance with the guidelines of the Commit-
University of Wisconsin Medical School, Madison, Wisconsin. 1 Supported by Pulmonary SCOR Grant No. HL19170and Training Grant No. HL-07633 from the National Heart, Lung and Blood Institute. 3 Presented in part at the Annual Meeting of the American Thoracic Society, Las Vegas, May 1988. 4 Correspondence and requests for reprints should be addressed to Richard M. Schwartzstein, M.D., Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. 419
420 spectrometer (Medical Gas Analyzer 1100; Perkin-Elmer, Pomona, CA). Inspiratory flow, measured with a Fleisch #3 pneumotachograph, was displayed on a storage oscilloscope and recorded with an eight-channel recorder (Hewlett-Packard, Waltham, MA). The flow signal was integrated with a respiratory integrator (Hewlett-Packard, Waltham, MA) to provide a continuous record of tidal volume. Respiratory pattern, that is, breathing frequency and duty cycle (the ratio of inspiratory time to the total time of the respiratory cycle, or Tt/Ttot), and mean inspiratory flow (VT/n) were derived from the flow signal. Initially subjects breathed with a tightfitting continuous positive airway pressure (CPAP) mask (dead space 120 ml) attached to an Otis valve. During the last 30 s of this initial4-min breathing trial, we stored the flow signal on the oscilloscope. In all subsequent trials, subjects matched their breathing to this pattern, thereby maintaining a constant ventilation and respiratory pattern. After a 10-min rest, subjects performed eight trials. During four of these trials, the subject breathed with the CPAP mask (M). In the other four trials, the buccal portion of a low-resistance (0.4 to 0.5 em H 20/L/s) mouthpiece (11) was placed in the subject's mouth and the subject breathed with the mask and mouthpiece (MM). The subject breathed alternately with M or MM; the initial condition was chosen at random. Care was taken not to occlude the nares. The subjects were not instructed on breathing preferentially through either the nose or the mouth. During each of the trials, we controlled the pattern of breathing by having the subjects match the initial pattern stored on the oscilloscope. Each trial lasted 4 min. Using a modified Borg scale (12), subjects rated the intensity of their "breathlessness," that is, the unpleasant sensation of breathing associated with the task, at the end of each trial. A 10-min rest period separated the trials. Of the 10 subjects 6 repeated the protocol on 2 additional days. On 1 day, the protocol was modified by warming (34 0 C) and humidifying the inspired gas. On the other day, we anesthetized the oral and buccal mucosa by applying 4070 lidocaine with a cotton swab. We applied lidocaine until subjects were unable to detect light touch in these areas. Lidocaine was reapplied as needed between trials to ensure the adequacy of the anesthesia. An additional protocol wasincluded to confirm that forces were similar in addition to breathing patterns between the two conditions (M and MM). Resistance of the total airways (and tissues) was measured as total pulmonary resistance (RL) in two subjects while they were breathing with a resistive load and hypercapnia with either M or MM as described previously (two trials each). RL was measured at peak esophageal pressure as determined with a 10-cmlatex balloon catheter swallowed into the lower esophagus. Using the technique of von Neergaard and Wirz (13), lung elastic pressure wassubtracted from total intrapleural
SIMON, BASNER, WEINBERGER, FENCL, WEISS, AND SCHWARTZSTEIN
TABLE 1 PATIERN OF BREATHING* Mask + Mouthpiece (MM)
Mask (M)
VE, Umin f, breaths/min TllTtot VT/TI, Us
19.9 17.4 0.58 0.58
± 6.6 ± 4.9 ± 0.05
± 0.14
Definition of abbreviations: respiratory frequency; Tlrrtot = mean inspiratory flow. • Values are mean ± SO.
19.8 ± 6.8 17.4 ± 4.9 0.56 ± 0.06 0.59 ± 0.16
p NS NS < 0.03 NS
VE =
minute ventilation; f = = inspiratory duty cycle; VTfTI
pressure to obtain the resistive pressure. RL was calculated by dividing resistive pressure by flow.
Data Analysis Data are presented as the mean ± SD. A t test for paired variates (14) was used.
Results By reproducing the flow tracing displayed on the oscilloscope, subjects matched total ventilation and pattern of breathing quite well from one trial to another. The mean values for minute ventilation, respiratory frequency, duty cycle, and mean inspiratory flow during M and MM are listed in table 1. Although the difference between the mean values of duty cycle did reach statistical significance (0.58 ± 0.05 for M and 0.56 ± 0.06 for MM), the difference was so small as to be of questionable physiologic importance. The breathlessness ratings for individual subjects are shown in figure 1.
The mean values were significantly higher for MM than for M (6.6 ± 1.1 for MM, 5.6 ± 1.8 for M; p < 0.01) and for the subgroup of six subjects who later repeated the protocol with additional interventions (table 2) (6.2 ± 0.9 for MM, 4.8 ± 1.1 for M; p < 0.01). When the protocol was repeated with inhalation of warm humidified air, there was no longer a difference in breathlessness ratings between MM and M (6.6 ± 1.4 for MM, 6.3 ± 1.2 for M; p >0.05) (figure 2). Similarly, the application of topical lidocaine to the oral mucosa abolished the differences in breathlessness between the two breathing conditions (mean rating 5.8 ± 1.0 for MM, 5.3 ± 0.5 for M; p > 0.05) (figure 3). In summary, subjects experienced a small but significant increase in breathlessness when breathing with a mask and mouthpiece compared with the mask alone. This difference was abolished by interventions that blocked or reduced the stimulation of these oral mucosal receptors (table 2). To evaluate possible differences between forces applied during breathing with a mask and during breathing with a mouthpiece, total pulmonary resistance was measured in two subjects. There was no significant difference in peak pressure (19.1 ± 1.5 em HzO for M versus 19.4 ± 1.6 em H 20 for MM and 28.8 ± 4.9 em H 20 for M versus 32.0 ± 4.2 em H 20 for MM) or mean RL between the two conditions (17.4 ± 0.2 em H 20/L/s for Mversus 17.5 ± l.4cmH 20/L/sforMM and 14.7 ± 1.6 em H 20/L/s for M versus 15.4 ± 0.3 em H 2 0 / L / s for MM.
10
01...---....1..------....1..---Mask
Mask+Mouthpiece
Fig. 1. Breathlessness ratings for individual subjects (n = 10) when breathing with the mask (M) compared with breathing with the mask and mouthpiece (MM). The bar indicates the mean value for each condition. The breathlessness ratings were significantly greater with MM compared with M (6.6 ± 1.1 for MM, 5.6 ± 1.8 for M; p < O.Q1, mean ± SO).
Discussion The results of this study show that insertion of a mouthpiece causes a small but significant increase in breathlessness elicited with hypercapnia combined with an inspiratory resistive load compared with breathing with a mask alone. Differences in minute ventilation or breathing pattern cannot explain these findings because these variables were kept constant. Inhalation of warm, humidified air and anesthesia of the oral mucosa abolished the differences in breathlessness between MM and M. Hirsch and Bishop (l) reported that normal subjects feel "more comfortable" when breathing with a mask than with a mouthpiece. In that study subjects did not systematically rate breathlessness, however, and the total ventilation and the pattern of breathing were not controlled. The authors reported that the increase in VE and respiratory frequency f with
ORAL MUCOSAL STIMULATION MODULATES BREATHLESSNESS IN NORMAL SUBJECTS
421
TABLE 2 BREATHLESSNESS RATINGS Warm Humidified Air
No Intervention Subject· JG
KP TS
TW DH
Cc Mean ± SO
Oral Anesthesia
M
MM
M
MM
M
MM
4.3 5.3 6.8 4.5 4.3 3.5
6.0 5.3 8.0 6.0 5.8 6.0
8.3 6.0 5.3 7.0 5.7 5.3
8.0 6.3 6.3 7.5 4.3 5.0
5.0 5.8 5.5 5.8 4.8 4.8
6.5 6.0 6.2 6.8 5.0 4.3
4.8 1.1
6.2t 0.9
6.3 1.2
6.6; 1.4
5.3 0.5
5.8; 1.0
Definition of abbreviations: M = mask; MM = mask and mouthpiece. • Only subjects who completed all three parts of the protocol are included. t Significantly different from mask, same conditions; p < 0.01. :j:Not significantly different from mask, same conditions.
hypercapnia and hypoxia was exaggerated by inserting a mouthpiece. This finding raises the possibility that greater breathlessness with a mouthpiece in place is provoked by an increase in the neuromotor output of the respiratory system, rather than by changes in afferent information from receptors in the oral mucosa. In our study, however, the subjects' total ventilation and pattern of breathing were the same with M and MM; thus, changes in respiratory drive are unlikely to explain the difference in breathlessness perceived during M and MM. Chonan and coworkers (15) and Schwartzstein's group (16) have shown that subjects forced to constrain their ventilation when stimulated with CO 2 report a greater intensity of breathlessness
than when they are allowed to breathe freely at the same PETCOz* If the placement of a mouthpiece called for an increased VE and we prevented subjects from responding in this manner by forcing them to adhere to a specific breathing target, it is possible that we were producing breathlessness by instructing subjects to suppress' their ventilation. However, Rodenstein and colleagues (6, 17)have demonstrated that most normal subjects do not increase VE when breathing through a mouthpiece if the nares are left unoccluded. In the studies cited previously (1-3) that showed an increase in VE with the use of a mouthpiece, subjects also had a noseclip in place. In our study, the nares werenot occluded. Thus, we believe it is unlikely that our subjects
10
-
Q.)
0
u
8
en
10
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CO
6
(/) (/) Q.)
c:: (/) (/)
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-0:-
:::::==----=LD..
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Mask
Mask +Mouthpiece
Fig. 2. Breathlessness ratings for individual subjects when inspiring warm humidified air and breathing with the mask (M) or with the mask and mouthpiece (MM). The bar indicates the mean value for each condition. Breathlessness ratings were not significantly different between the two groups (6.6 ± 1.4 for MM, 6.3 ± 1.2 for M; NS, mean ± SO).
0 Mask
Mask+ Mouthpiece
Fig. 3. Breathlessness ratings for individual subjects after topical application of 4% lidocaine to the oral mucosa. The bar indicates the mean value for each condition. With oral anesthesia there was no significant difference in subjects' breathlessness ratings when breathing with a mask compared with a mask and mouthpiece (5.3 ± 0.5 for M, 5.8 ± 1.0 for MM; NS, mean ± SO).
were suppressing their ventilation by following the pattern displayed on the oscilloscope. Despite matching breathing patterns, we cannot be certain that the same forces wereapplied when subjects breathed with the different conditions. We, therefore, measured peak pressure and total pulmonary resistance in two subjects following the same protocol of matching breathing pattern while breathing either with a mask or a mask and mouthpiece. We found no significant difference in peak pressure or total pulmonary resistancebetween the two conditions. Furthermore, we would not have expected to see differences in breathlessness between M and MM abolished by either oral mucosal anesthesia or warm humidified air had the effect been caused by differences in forces applied during breathing with the different conditions. However, we cannot exclude the possibility that the effects of these interventions on breathlessness werethrough different mechanisms. A flow of air through the nose reduces the ventilatory response to hypercapnia (7, 8) and prolongs breath-holding time (9). If the use of a mouthpiece resulted in a shift from nasal to oral breathing, the attendant decrease in nasal flow and the resultant increase in neuromuscular output associated with MM relative to M might explain the increase in the intensity of breathlessness. Although Cole and colleagues (11) have demonstrated that usc of a mouthpiece reduces oral resistance by up to 80070, most normal subjects continue to breathe through the nose despite having an open mouth (6, 17). One would not have expected the differences in breathlessness ratings between M and MM to have been abolished by oral anesthesia if the effect were due to changes in nasal flow. Furthermore, Liss and Grant (18) found that breathlessness was not alleviated in patients with COPD when flow through the nose was increased with nasal prongs. Therefore, we do not believe that changes in nasal flow between M and MM could account for our results. Inhalation of aerosolized lidocaine has been shown to increase the ventilatory response to hypercapnia (19, 20) but to decrease the resting ventilation in normal subjects (21). These effects are presumed to be caused by alterations in pulmonary receptors. We applied lidocaine to the oral mucosa of our subjects with a cotton-tipped swab; it is improbable that any significant quantity of lidocaine reached the lungs. Patients with COPD and dyspnea
SIMON, BASNER, WEINBERGER, FENCL, WEISS, AND SCHWAATZSTEIN
422
commonlyreport reliefof symptomswhen seated in front of a fan. Schwartzstein and coworkers (10) have shown that in normal subjects the flow of cold air to the face reduces the intensity of breathlessness associated with hypercapniacombined with an inspiratory resistive load; VE was not altered by this intervention. These clinical and experimental observations could be explained by postulating that increased afferent information from receptors innervated by the trigeminal nerve has a salutary effect on dyspnea. Conversely, a reduction in afferent information from these receptors would increase the intensity of breathlessness. Tothe extent that a mouthpiece blocks a portion of the oral mucosa from the flow of gas entering and exiting the trachea, it may reduce afferent information from flow receptors in the mucosa, and increase breathlessness. By reducing afferent information from these flow receptorsequally during M and MM, topical anesthesia of the oral mucosa should abolish the differences in breathlessness between these two conditions. Similarly, inhalation of warm, humidified air would diminish stimulation of the flow receptors and thus eliminate the differences in breathlessness between M and MM. Thus, our data support the hypothesis that stimulation of oral mucosal recep-
tors modulates the intensity of breathlessness independently of changes in ventilation or pattern of breathing. References 1. Hirsch lA, Bishop B. Human breathing pat-
terns on mouthpiece or face mask during air, CO 2 , or low O 2 • J Appl Physiol 1982; 53:1281-90. 2. Weissman C, Askanazi J, Milk-Emili J, Kinney JM. Effect of respiratory apparatus on respiration. J Appl Physiol 1984; 57:475-80. 3. Perez W, Tobin MJ. Separation of factors responsible for change in breathing pattern induced by instrumentation. J Appl Physiol 1985; 59: 1515-20. 4. Western PJ, Patrick JM. Effects of focusing attention on breathing with and without apparatus on the face. Respir Physiol 1988; 72:123-30. 5. Douglas NJ, White DP, WeilJV, Zwillich CWo Effect of breathing route on ventilation and ventilatory drive. Respir Physiol 1983; 51:209-18. 6. Rodenstein DO, Mercenier C, Stanescu DC. Influence of the respiratory route on the restingbreathing pattern in humans. Am Rev Respir Dis 1985; 131:163-6. 7. Burgess KR, Whitelaw WA. Reducing ventilatory response to carbon dioxide by breathing cold air. Am Rev Respir Dis 1984; 129:687-90. 8. Burgess KR, Whitelaw WA. Effects of nasal cold receptors on pattern of breathing. J Appl Physiol 1988; 64:371-6 9. McBride B, Whitelaw· WA. A physiological stimulus to upper airway receptors in humans. J Appl Physiol 1981; 51:1189-97. 10. Schwartzstein RM, LaHive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis 1987; 136:58-61. 11. Cole P, Forsyth R, Haight JSJ. Respiratory
resistance of the oral airway. Am Rev Respir Dis 1982; 125:363-5. 12. Altose MD. Dyspnea. In: Simmons DH, ed. Current pulmonology. New York: YearBook Medical Publishers, 1986; 199-226. 13. von Neergaard J, Wirz K. Die messung der stromungswiderstande in den atemwegen des menschen, insbesondere bei asthma und emphysem, Z Klin Med 1927; 105:51-82. 14. Glantz SA. Biostatistics. New York: McGrawHill, 1981; 63-90. 15. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822-8. 16. Schwartzstein RM, Simon PM, Weiss JW. Fencl V. Weinberger SE. Breathlessness induced by dissociation betweenventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231-7. 17. Rodenstein DO, Stanescu DC. Soft palate and oronasal breathing in humans. J Appl Physiol1984; 57:651-7. 18. Liss HP. Grant BJB.The effect of nasal flow on breathlessness in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 137:1285-8. 19. Sullivan TY, DeWeese EL, Yu P-L, Aronoff GR. Ventilatory response during CO 2 inhalation after airway anesthesia with lidocaine. J Appl Physiol 1986; 61:2230-7. 20. Sullivan TY. DeWeese EL, Yu P-L, Aronoff GR. Lung mechanics and neuromuscular output during COl inhalation after airway anesthesia. J Appl Physiol 1987; 63:2542-8. 21. Savoy J, Dhingra S. Anthonisen NR. Inhaled lidocaine aerosol changes resting human breathing pattern. Respir Physiol 1982; 50:41-9.
PEGGY M. SIMON, ROBERT C. BASNER, STEVEN E. WEINBERGER, VLADIMIR FENCL,
J. WOODROW WEISS, and RICHARD M. SCHWARTZSTEIN
Introduction
Patients with chronic obstructive lung disease (COPD) have often been observed to complain of severe dyspnea when a mouthpiece is used in the performance of pulmonary function tests. When normal subjects breathe through a mouthpiece, their respiratory neuromuscular output is generally increased, as evidenced by increases in minute ventilation (VE), tidal volume (VT), and mean inspiratory flow (VT/TI) (1-3). The respiratory pattern also changes (1, 3). Western and Patrick suggested that awareness of breathing could account for the changes in inspiratory pattern observed when a mask is applied to the face (4). However, other studies indicate that the shift from nasal to oral or oronasal respiration with a mouthpiece stimulates receptors in the nose, mouth, and pharynx, leading to changes in ventilation and breathing pattern (5, 6). The flow of cold air through the nose has been associated with a reduction in the ventilatory response to hypercapnia (7, 8) and prolongation of breath-holding time (9). From these findings, one might conclude that the dyspnea perceived by patients with COPD when breathing through a mouthpiece is provoked by an increased neuromuscular output. An alternative to this hypothesis is that the increased dyspnea associated with the mouthpiece is due to changes in afferent information from oral receptors. A study in normal subjects (10) showed that the flow of cold air on the face reduces breathlessness associated with hypercapnia and inspiratory resistive loading (presumably stimulating receptors that, like the buccal mucosa, are innervated by the trigeminal nerve). The purpose of our study was to determine whether stimulation of receptors in the oral mucosa decreases the sensation of breathlessness independently of changes in ventilation and pattern of breathing. We hypothesized that breathing through a mouthpiece would bypass
SUMMARY Patients with chronic obstructive pUlmonary disease (COPO)often report an Increase In breathle..ness when they breathe through a mouthpiece. We hypoth.slzed that stimulation of receptors In the oral mucosa modulat.s the sensation of breathl...n.... W. studied 10 normal naive volunteers In whom breathl ...ne.. was Induced by having th.m breath. for 4 min with an Inspiratory resistive load (18 em H 20/Us) while breathing was stimulated by CO2 Inhalation (.ndtidal PC0 2 maintained at 55 mm Hg). Initially, subjects breath.d with a tight-fitting face mask and Inspiratory flow was displayed on a storage oscilloscope. In subsequent trials, the subjects were asked to match this trace, which controlled ventilation and the pattern of breathing. Subjects performed eight trials, four with the tight-fitting mask only (M) and four with a mouthpiece and the mask (MM). M and MM were alternated; the Initial condition was chosen at random. following each of the trials, subjects rated the Intensity of their breathle..ne.. by choosing a number from a modified Borg scale. On the average, subjects were more breathless while breathing with the mask and mouthpiece than with ttie mask alone (mean ratings of breathle..ne.. 6.6 ± 1.1 and 5.6 ± 1.8 units, p < 0.01). Six subjects repeated the protocol on 2 additional days: 1 dllY with Inhalation of warm (340 C), humidified air and 1 dllY after toplcel application of 4% lidocaine to the oral mucosa. Both these Interventions abolished the differences In breathl...n... between mask and mouthpiece and mask alone. Weconclude that afferent Information from oral mucosal stimulation Influences AM REV RESPIR DIS 1991; 144:419-422 the Intensity of breathlessne...
these "flow receptors," resulting in an in- tee on Clinical Investigations at the Beth Israel Hospital. crease in breathlessness. Reducing the stimulation of these flow receptors by Protocol anesthesia or warm, humidified air would ' Nine trials were performed during each of the have a similar effect on breathlessness. three study sessions. During each trial subTo test this hypothesis, we studied in nor- jects inspired for 4 min through a resistive mal subjects the effect of breathing load (18 em H 20/L/s, between 0.5 and 1.5 through a mask (M) or through a mask Lis, created with sintered filters) while CO 2 and mouthpiece (MM) on the breathless- was added to the inspired gas to maintain the ness produced by hypercapnia combined end-tidal partial pressure of carbon dioxide with an inspiratory resistive load. Simi- (PETeo2) at 55 mm Hg. End-tidal Pco, was monitored with a mass larly, breathlessness ratings were compared between the two breathing conditions (M and MM) after oral mucosal anesthesia and inhalation of warm, hu- (Received in original form November ~ 1989 and midified air on 2 separate days. Minute in revised form January 2, 1991) ventilation and respiratory pattern were From the Charles A. Dana Research Institute controlled to eliminate changes in neuand the Harvard-Thorndike Laboratory, Beth isromuscular output as an explanation for rael Hospital; the Department of Medicine, Beth differences in breathlessness between Israel Hospital and Harvard Medical School, Bosbreathing with a mask or a mask and ton, Massachusetts; and the Department of Medicine, Wm. S. Middleton Memorial VAHospital and mouthpiece. 1
Methods Subjects A group of 10 naive normal volunteers were recruited from local colleges. The ages of the subjects ranged from 18 to 33 yr. No subject had a history of pulmonary or cardiac disease. Informed consent was obtained in accordance with the guidelines of the Commit-
University of Wisconsin Medical School, Madison, Wisconsin. 1 Supported by Pulmonary SCOR Grant No. HL19170and Training Grant No. HL-07633 from the National Heart, Lung and Blood Institute. 3 Presented in part at the Annual Meeting of the American Thoracic Society, Las Vegas, May 1988. 4 Correspondence and requests for reprints should be addressed to Richard M. Schwartzstein, M.D., Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. 419
420 spectrometer (Medical Gas Analyzer 1100; Perkin-Elmer, Pomona, CA). Inspiratory flow, measured with a Fleisch #3 pneumotachograph, was displayed on a storage oscilloscope and recorded with an eight-channel recorder (Hewlett-Packard, Waltham, MA). The flow signal was integrated with a respiratory integrator (Hewlett-Packard, Waltham, MA) to provide a continuous record of tidal volume. Respiratory pattern, that is, breathing frequency and duty cycle (the ratio of inspiratory time to the total time of the respiratory cycle, or Tt/Ttot), and mean inspiratory flow (VT/n) were derived from the flow signal. Initially subjects breathed with a tightfitting continuous positive airway pressure (CPAP) mask (dead space 120 ml) attached to an Otis valve. During the last 30 s of this initial4-min breathing trial, we stored the flow signal on the oscilloscope. In all subsequent trials, subjects matched their breathing to this pattern, thereby maintaining a constant ventilation and respiratory pattern. After a 10-min rest, subjects performed eight trials. During four of these trials, the subject breathed with the CPAP mask (M). In the other four trials, the buccal portion of a low-resistance (0.4 to 0.5 em H 20/L/s) mouthpiece (11) was placed in the subject's mouth and the subject breathed with the mask and mouthpiece (MM). The subject breathed alternately with M or MM; the initial condition was chosen at random. Care was taken not to occlude the nares. The subjects were not instructed on breathing preferentially through either the nose or the mouth. During each of the trials, we controlled the pattern of breathing by having the subjects match the initial pattern stored on the oscilloscope. Each trial lasted 4 min. Using a modified Borg scale (12), subjects rated the intensity of their "breathlessness," that is, the unpleasant sensation of breathing associated with the task, at the end of each trial. A 10-min rest period separated the trials. Of the 10 subjects 6 repeated the protocol on 2 additional days. On 1 day, the protocol was modified by warming (34 0 C) and humidifying the inspired gas. On the other day, we anesthetized the oral and buccal mucosa by applying 4070 lidocaine with a cotton swab. We applied lidocaine until subjects were unable to detect light touch in these areas. Lidocaine was reapplied as needed between trials to ensure the adequacy of the anesthesia. An additional protocol wasincluded to confirm that forces were similar in addition to breathing patterns between the two conditions (M and MM). Resistance of the total airways (and tissues) was measured as total pulmonary resistance (RL) in two subjects while they were breathing with a resistive load and hypercapnia with either M or MM as described previously (two trials each). RL was measured at peak esophageal pressure as determined with a 10-cmlatex balloon catheter swallowed into the lower esophagus. Using the technique of von Neergaard and Wirz (13), lung elastic pressure wassubtracted from total intrapleural
SIMON, BASNER, WEINBERGER, FENCL, WEISS, AND SCHWARTZSTEIN
TABLE 1 PATIERN OF BREATHING* Mask + Mouthpiece (MM)
Mask (M)
VE, Umin f, breaths/min TllTtot VT/TI, Us
19.9 17.4 0.58 0.58
± 6.6 ± 4.9 ± 0.05
± 0.14
Definition of abbreviations: respiratory frequency; Tlrrtot = mean inspiratory flow. • Values are mean ± SO.
19.8 ± 6.8 17.4 ± 4.9 0.56 ± 0.06 0.59 ± 0.16
p NS NS < 0.03 NS
VE =
minute ventilation; f = = inspiratory duty cycle; VTfTI
pressure to obtain the resistive pressure. RL was calculated by dividing resistive pressure by flow.
Data Analysis Data are presented as the mean ± SD. A t test for paired variates (14) was used.
Results By reproducing the flow tracing displayed on the oscilloscope, subjects matched total ventilation and pattern of breathing quite well from one trial to another. The mean values for minute ventilation, respiratory frequency, duty cycle, and mean inspiratory flow during M and MM are listed in table 1. Although the difference between the mean values of duty cycle did reach statistical significance (0.58 ± 0.05 for M and 0.56 ± 0.06 for MM), the difference was so small as to be of questionable physiologic importance. The breathlessness ratings for individual subjects are shown in figure 1.
The mean values were significantly higher for MM than for M (6.6 ± 1.1 for MM, 5.6 ± 1.8 for M; p < 0.01) and for the subgroup of six subjects who later repeated the protocol with additional interventions (table 2) (6.2 ± 0.9 for MM, 4.8 ± 1.1 for M; p < 0.01). When the protocol was repeated with inhalation of warm humidified air, there was no longer a difference in breathlessness ratings between MM and M (6.6 ± 1.4 for MM, 6.3 ± 1.2 for M; p >0.05) (figure 2). Similarly, the application of topical lidocaine to the oral mucosa abolished the differences in breathlessness between the two breathing conditions (mean rating 5.8 ± 1.0 for MM, 5.3 ± 0.5 for M; p > 0.05) (figure 3). In summary, subjects experienced a small but significant increase in breathlessness when breathing with a mask and mouthpiece compared with the mask alone. This difference was abolished by interventions that blocked or reduced the stimulation of these oral mucosal receptors (table 2). To evaluate possible differences between forces applied during breathing with a mask and during breathing with a mouthpiece, total pulmonary resistance was measured in two subjects. There was no significant difference in peak pressure (19.1 ± 1.5 em HzO for M versus 19.4 ± 1.6 em H 20 for MM and 28.8 ± 4.9 em H 20 for M versus 32.0 ± 4.2 em H 20 for MM) or mean RL between the two conditions (17.4 ± 0.2 em H 20/L/s for Mversus 17.5 ± l.4cmH 20/L/sforMM and 14.7 ± 1.6 em H 20/L/s for M versus 15.4 ± 0.3 em H 2 0 / L / s for MM.
10
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Fig. 1. Breathlessness ratings for individual subjects (n = 10) when breathing with the mask (M) compared with breathing with the mask and mouthpiece (MM). The bar indicates the mean value for each condition. The breathlessness ratings were significantly greater with MM compared with M (6.6 ± 1.1 for MM, 5.6 ± 1.8 for M; p < O.Q1, mean ± SO).
Discussion The results of this study show that insertion of a mouthpiece causes a small but significant increase in breathlessness elicited with hypercapnia combined with an inspiratory resistive load compared with breathing with a mask alone. Differences in minute ventilation or breathing pattern cannot explain these findings because these variables were kept constant. Inhalation of warm, humidified air and anesthesia of the oral mucosa abolished the differences in breathlessness between MM and M. Hirsch and Bishop (l) reported that normal subjects feel "more comfortable" when breathing with a mask than with a mouthpiece. In that study subjects did not systematically rate breathlessness, however, and the total ventilation and the pattern of breathing were not controlled. The authors reported that the increase in VE and respiratory frequency f with
ORAL MUCOSAL STIMULATION MODULATES BREATHLESSNESS IN NORMAL SUBJECTS
421
TABLE 2 BREATHLESSNESS RATINGS Warm Humidified Air
No Intervention Subject· JG
KP TS
TW DH
Cc Mean ± SO
Oral Anesthesia
M
MM
M
MM
M
MM
4.3 5.3 6.8 4.5 4.3 3.5
6.0 5.3 8.0 6.0 5.8 6.0
8.3 6.0 5.3 7.0 5.7 5.3
8.0 6.3 6.3 7.5 4.3 5.0
5.0 5.8 5.5 5.8 4.8 4.8
6.5 6.0 6.2 6.8 5.0 4.3
4.8 1.1
6.2t 0.9
6.3 1.2
6.6; 1.4
5.3 0.5
5.8; 1.0
Definition of abbreviations: M = mask; MM = mask and mouthpiece. • Only subjects who completed all three parts of the protocol are included. t Significantly different from mask, same conditions; p < 0.01. :j:Not significantly different from mask, same conditions.
hypercapnia and hypoxia was exaggerated by inserting a mouthpiece. This finding raises the possibility that greater breathlessness with a mouthpiece in place is provoked by an increase in the neuromotor output of the respiratory system, rather than by changes in afferent information from receptors in the oral mucosa. In our study, however, the subjects' total ventilation and pattern of breathing were the same with M and MM; thus, changes in respiratory drive are unlikely to explain the difference in breathlessness perceived during M and MM. Chonan and coworkers (15) and Schwartzstein's group (16) have shown that subjects forced to constrain their ventilation when stimulated with CO 2 report a greater intensity of breathlessness
than when they are allowed to breathe freely at the same PETCOz* If the placement of a mouthpiece called for an increased VE and we prevented subjects from responding in this manner by forcing them to adhere to a specific breathing target, it is possible that we were producing breathlessness by instructing subjects to suppress' their ventilation. However, Rodenstein and colleagues (6, 17)have demonstrated that most normal subjects do not increase VE when breathing through a mouthpiece if the nares are left unoccluded. In the studies cited previously (1-3) that showed an increase in VE with the use of a mouthpiece, subjects also had a noseclip in place. In our study, the nares werenot occluded. Thus, we believe it is unlikely that our subjects
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Fig. 2. Breathlessness ratings for individual subjects when inspiring warm humidified air and breathing with the mask (M) or with the mask and mouthpiece (MM). The bar indicates the mean value for each condition. Breathlessness ratings were not significantly different between the two groups (6.6 ± 1.4 for MM, 6.3 ± 1.2 for M; NS, mean ± SO).
0 Mask
Mask+ Mouthpiece
Fig. 3. Breathlessness ratings for individual subjects after topical application of 4% lidocaine to the oral mucosa. The bar indicates the mean value for each condition. With oral anesthesia there was no significant difference in subjects' breathlessness ratings when breathing with a mask compared with a mask and mouthpiece (5.3 ± 0.5 for M, 5.8 ± 1.0 for MM; NS, mean ± SO).
were suppressing their ventilation by following the pattern displayed on the oscilloscope. Despite matching breathing patterns, we cannot be certain that the same forces wereapplied when subjects breathed with the different conditions. We, therefore, measured peak pressure and total pulmonary resistance in two subjects following the same protocol of matching breathing pattern while breathing either with a mask or a mask and mouthpiece. We found no significant difference in peak pressure or total pulmonary resistancebetween the two conditions. Furthermore, we would not have expected to see differences in breathlessness between M and MM abolished by either oral mucosal anesthesia or warm humidified air had the effect been caused by differences in forces applied during breathing with the different conditions. However, we cannot exclude the possibility that the effects of these interventions on breathlessness werethrough different mechanisms. A flow of air through the nose reduces the ventilatory response to hypercapnia (7, 8) and prolongs breath-holding time (9). If the use of a mouthpiece resulted in a shift from nasal to oral breathing, the attendant decrease in nasal flow and the resultant increase in neuromuscular output associated with MM relative to M might explain the increase in the intensity of breathlessness. Although Cole and colleagues (11) have demonstrated that usc of a mouthpiece reduces oral resistance by up to 80070, most normal subjects continue to breathe through the nose despite having an open mouth (6, 17). One would not have expected the differences in breathlessness ratings between M and MM to have been abolished by oral anesthesia if the effect were due to changes in nasal flow. Furthermore, Liss and Grant (18) found that breathlessness was not alleviated in patients with COPD when flow through the nose was increased with nasal prongs. Therefore, we do not believe that changes in nasal flow between M and MM could account for our results. Inhalation of aerosolized lidocaine has been shown to increase the ventilatory response to hypercapnia (19, 20) but to decrease the resting ventilation in normal subjects (21). These effects are presumed to be caused by alterations in pulmonary receptors. We applied lidocaine to the oral mucosa of our subjects with a cotton-tipped swab; it is improbable that any significant quantity of lidocaine reached the lungs. Patients with COPD and dyspnea
SIMON, BASNER, WEINBERGER, FENCL, WEISS, AND SCHWAATZSTEIN
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commonlyreport reliefof symptomswhen seated in front of a fan. Schwartzstein and coworkers (10) have shown that in normal subjects the flow of cold air to the face reduces the intensity of breathlessness associated with hypercapniacombined with an inspiratory resistive load; VE was not altered by this intervention. These clinical and experimental observations could be explained by postulating that increased afferent information from receptors innervated by the trigeminal nerve has a salutary effect on dyspnea. Conversely, a reduction in afferent information from these receptors would increase the intensity of breathlessness. Tothe extent that a mouthpiece blocks a portion of the oral mucosa from the flow of gas entering and exiting the trachea, it may reduce afferent information from flow receptors in the mucosa, and increase breathlessness. By reducing afferent information from these flow receptorsequally during M and MM, topical anesthesia of the oral mucosa should abolish the differences in breathlessness between these two conditions. Similarly, inhalation of warm, humidified air would diminish stimulation of the flow receptors and thus eliminate the differences in breathlessness between M and MM. Thus, our data support the hypothesis that stimulation of oral mucosal recep-
tors modulates the intensity of breathlessness independently of changes in ventilation or pattern of breathing. References 1. Hirsch lA, Bishop B. Human breathing pat-
terns on mouthpiece or face mask during air, CO 2 , or low O 2 • J Appl Physiol 1982; 53:1281-90. 2. Weissman C, Askanazi J, Milk-Emili J, Kinney JM. Effect of respiratory apparatus on respiration. J Appl Physiol 1984; 57:475-80. 3. Perez W, Tobin MJ. Separation of factors responsible for change in breathing pattern induced by instrumentation. J Appl Physiol 1985; 59: 1515-20. 4. Western PJ, Patrick JM. Effects of focusing attention on breathing with and without apparatus on the face. Respir Physiol 1988; 72:123-30. 5. Douglas NJ, White DP, WeilJV, Zwillich CWo Effect of breathing route on ventilation and ventilatory drive. Respir Physiol 1983; 51:209-18. 6. Rodenstein DO, Mercenier C, Stanescu DC. Influence of the respiratory route on the restingbreathing pattern in humans. Am Rev Respir Dis 1985; 131:163-6. 7. Burgess KR, Whitelaw WA. Reducing ventilatory response to carbon dioxide by breathing cold air. Am Rev Respir Dis 1984; 129:687-90. 8. Burgess KR, Whitelaw WA. Effects of nasal cold receptors on pattern of breathing. J Appl Physiol 1988; 64:371-6 9. McBride B, Whitelaw· WA. A physiological stimulus to upper airway receptors in humans. J Appl Physiol 1981; 51:1189-97. 10. Schwartzstein RM, LaHive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis 1987; 136:58-61. 11. Cole P, Forsyth R, Haight JSJ. Respiratory
resistance of the oral airway. Am Rev Respir Dis 1982; 125:363-5. 12. Altose MD. Dyspnea. In: Simmons DH, ed. Current pulmonology. New York: YearBook Medical Publishers, 1986; 199-226. 13. von Neergaard J, Wirz K. Die messung der stromungswiderstande in den atemwegen des menschen, insbesondere bei asthma und emphysem, Z Klin Med 1927; 105:51-82. 14. Glantz SA. Biostatistics. New York: McGrawHill, 1981; 63-90. 15. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822-8. 16. Schwartzstein RM, Simon PM, Weiss JW. Fencl V. Weinberger SE. Breathlessness induced by dissociation betweenventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231-7. 17. Rodenstein DO, Stanescu DC. Soft palate and oronasal breathing in humans. J Appl Physiol1984; 57:651-7. 18. Liss HP. Grant BJB.The effect of nasal flow on breathlessness in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 137:1285-8. 19. Sullivan TY, DeWeese EL, Yu P-L, Aronoff GR. Ventilatory response during CO 2 inhalation after airway anesthesia with lidocaine. J Appl Physiol 1986; 61:2230-7. 20. Sullivan TY. DeWeese EL, Yu P-L, Aronoff GR. Lung mechanics and neuromuscular output during COl inhalation after airway anesthesia. J Appl Physiol 1987; 63:2542-8. 21. Savoy J, Dhingra S. Anthonisen NR. Inhaled lidocaine aerosol changes resting human breathing pattern. Respir Physiol 1982; 50:41-9.
