The Effect of Aerosol Saline on Laboratory-Induced Dyspnea.

PURPOSE: In the 'placebo arm' of a recent study, we found that aerosol saline (sham treatment) produced substantial relief of laboratory-induced dyspnea (Breathing discomfort-BD) in nearly half the subjects. The sham intervention included a physiological change, and instructions to subjects could have produced expectation of dyspnea relief. In the present study, we attempted to discover whether the response to sham aerosol was driven by behavioral or physiological aspects of the intervention. METHODS: Dyspnea (air hunger) was evoked by constraining tidal volume during graded hypercapnia. We measured [Formula: see text] versus BD relationship before and after aerosol saline. To minimize subjects' expectations of dyspnea relief, participants were clearly instructed that we would only deliver saline aerosol. In Protocol 1, we delivered aerosol saline with a ventilator (mimicking our prior study); in Protocol 2, we delivered aerosol without a ventilator. RESULTS: Administration of aerosol saline had little effect on BD in this group of subjects with one exception: one subject experienced appreciable reduction in BD in Protocol 1. This treatment effect was less in Protocol 2. The two most likely explanations are (a) that procedures surrounding ventilator administration of aerosol produced a psychological placebo treatment effect even though the subject knew a drug was not given; (b) there were behavioral changes in breathing undetected by our measurements of respiratory flow and volume that altered the subjects comfort. CONCLUSION: When the expectation of treatment effect is minimized, a significant reduction in dyspnea in response to saline placebo is uncommon but not impossible.

Descriptors of breathlessness in healthy individuals: distinct and separable constructs.

STUDY OBJECTIVES: We tested the hypothesis that descriptors of breathlessness represent distinct and separable cognitive constructs, and predicted that the use of descriptors of breathlessness by healthy individuals is the same as their use by patients with cardiopulmonary disease. DESIGN: Cluster analyses obtained in healthy individuals were compared with those obtained previously in patients who complained of breathing discomfort. In addition, we used multidimensional scaling (MDS) techniques to analyze relationships among descriptors in healthy individuals. SETTING: Public university. PARTICIPANTS: The participants were 100 healthy individuals (48 men and 52 women) ranging in age between 18 and 65 years (mean, 27.9+/-11.7 years). MEASUREMENTS AND RESULTS: Participants judged the dissimilarity among pairs of 15 descriptors of breathlessness that were used previously to examine the experience of dyspnea in patients who complained of breathing discomfort. Cluster analysis solutions obtained in the healthy individuals were virtually identical to those obtained previously in patients. Three dimensions (attributes) of breathing discomfort were uncovered with MDS: "Depth and frequency of breathing," "Perceived need, or urge, to breathe," and "Difficulty breathing and phase of respiration." The results did not depend on age, sex, levels of education, or the presence of uncomfortable awareness of breathing with activities. CONCLUSIONS: The relations among descriptors of breathlessness obtained in healthy individuals support the contention that the association of different clusters with different disease states reflects distinct and separable cognitive constructs that are not simply dependent on the presence of an underlying pathophysiology or on a specific disease condition. Our results in healthy individuals also suggest that distinct qualities of breathlessness relate to different physiologic mechanisms underlying respiratory discomfort.

External thoracic restriction, respiratory sensation, and ventilation during exercise in men.

Multiple factors may contribute to the dyspnea associated with restrictive ventilatory disease (RVD). Simple models that examine specific features of this problem are likely to provide insight into the mechanisms. Previous models of RVD utilizing elastic loads may not represent completely the impact on pulmonary and chest wall receptors derived from breathing at low thoracic volumes. The purpose of this study was to investigate the sensory consequences of breathing at low lung volumes induced by external thoracic restriction in an attempt to further elucidate the etiology of dyspnea in this setting. Ten men were studied, with and without an inelastic corset applied at residual volume (restriction resulted in mean reductions in vital capacity, functional residual capacity, residual volume, and forced expired volume in 1 s of 44, 31, 12.5, and 42%, respectively). During 10-min steady-state exercise tests (at a workload set to achieve approximately 65% maximum heart rate), restriction resulted in significant increases, compared with control, in minute ventilation (61 vs. 49 l/min), respiratory frequency (43 vs. 23 breaths/min), and visual analog scale measurements of respiratory discomfort (65 vs. 20 mm). Alveolar hyperventilation (end-tidal PCO2 = 39 vs. 44 Torr for control) and mild O2 desaturation (arterial blood O2 saturation = 93 vs. 95% for control) occurred. Hypoxemia, atelectasis, increased work and effort of breathing, or a decrease in the volume-related feedback from chest wall and/or lungs could be responsible for the increased dyspnea reported. External thoracic restriction provides a useful model to study mechanisms of dyspnea in RVD.

Breathing route influences upper airway muscle activity in awake normal adults.

Both nasal obstruction and nasal anesthesia result in disordered breathing during sleep in humans, and bypassing the nasal route during tidal breathing in experimental animals produces decreased electromyographic activity of upper airway (UA) dilating muscles. To investigate UA responses to breathing route in normal awake humans, we studied eight healthy males (ages 21-38 yr) during successive trials of voluntary nose breathing (N), voluntary mouth breathing (M), and mouth breathing with nose occluded (MO). We measured genioglossus electromyographic activity (EMGgg) with perorally inserted bipolar electrodes, alae nasi (EMGan) and diaphragm EMG activity (EMGdi) with surface electrodes, and minute ventilation (VE) with a pneumotachograph. Mean phasic inspiratory EMG activity of both UA muscles was significantly greater during N than during M or MO, even when a 2.5-cmH2O.l-1.s inspiratory resistance was added to MO (P less than 0.01). In contrast, neither EMGdi nor VE was consistently affected by breathing route. EMGgg during N was significantly decreased after selective topical nasal anesthesia (P less than 0.002); a decrease in EMGan did not achieve statistical significance. These data suggest that peak UA dilating muscle activity may be modulated by superficial receptors in the nasal mucosa sensitive to airflow.

Effect of chest wall vibration on breathlessness in normal subjects.

This study evaluated the effect of chest wall vibration (115 Hz) on breathlessness. Breathlessness was induced in normal subjects by a combination of hypercapnia and an inspiratory resistive load; both minute ventilation and end-tidal CO2 were kept constant. Cross-modality matching was used to rate breathlessness. Ratings during intercostal vibration were expressed as a percentage of ratings during the control condition (either deltoid vibration or no vibration). To evaluate their potential contribution to any changes in breathlessness, we assessed several aspects of ventilation, including chest wall configuration, functional residual capacity (FRC), and the ventilatory response to steady-state hypercapnia. Intercostal vibration reduced breathlessness ratings by 6.5 +/- 5.7% compared with deltoid vibration (P less than 0.05) and by 7.0 +/- 8.3% compared with no vibration (P less than 0.05). The reduction in breathlessness was accompanied by either no change or negligible change in minute ventilation, tidal volume, frequency, duty cycle, compartmental ventilation, FRC, and the steady-state hypercapnic response. We conclude that chest wall vibration reduces breathlessness and speculate that it may do so through stimulation of receptors in the chest wall.

Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep.

Six healthy subjects (5 males and 1 female, 26-40 yr old) were studied during non-rapid-eye-movement (NREM) sleep to assess the role of upper airway (UA) afferents in the arousal response to induced airway occlusion. Subjects wore an airtight face mask attached to a low-resistance one-way valve. A valve in the inspiratory circuit allowed instantaneous inspiratory airway occlusion and release; the expiratory circuit remained unoccluded at all times. Each subject was studied during two nights. On one night, occlusions were created during stable stage 2 NREM sleep before and after application of 4% lidocaine to the oral and nasal mucosa. On the other night, the protocol was duplicated with saline ("sham anesthesia") rather than lidocaine. The order of nights was randomized. Occlusions were sustained until electroencephalographic arousal. Three to 12 occlusions were performed in each subject for each of the four parts of the protocol (pre- and post-lidocaine, pre- and post-saline). The auditory threshold for arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after UA lidocaine. For the group, arousal time after UA anesthesia was prolonged compared with preanesthesia arousal time (P less than 0.001); arousal time after sham anesthesia did not significantly increase from before sham anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was greater than the increase with sham anesthesia (P less than 0.001). The auditory arousal threshold did not increase after UA anesthesia. Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and end-tidal PCO2 during occlusions were similar before and after UA anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inspired air temperature on genioglossus activity during nose breathing in awake humans.

Experimental data suggest the presence of sensory receptors specific to the nasopharynx that may reflexly influence respiratory activity. To investigate the effects of inspired air temperature on upper airway dilator muscle activity during nose breathing, we compared phasic genioglossus electromyograms (EMGgg) in eight normal awake adults breathing cold dry or warm humidified air through the nose. EMGgg was measured with peroral bipolar electrodes during successive trials of cold air (less than or equal to 15 degrees C) and warm air (greater than or equal to 34 degrees C) nasal breathing and quantified for each condition as percent activity at baseline (room temperature). In four of the subjects, the protocol was repeated after topical nasal anesthesia. For all eight subjects, mean EMGgg was greater during cold air breathing than during baseline (P less than 0.005) or warm air breathing (P less than 0.01); mean EMGgg during warm air breathing was not significantly changed from baseline. Nasal anesthesia significantly decreased the mean EMGgg response to cold air breathing. Nasal airway inspiratory resistance, measured by posterior rhinomanometry in six subjects under similar conditions, was no different for cold or warm air nose breathing [cold 1.4 +/- 0.7 vs. warm 1.4 +/- 1.1 (SD) cmH2O.l-1.s at 0.4 l/s flow]. These data suggest the presence of superficially located nasal cold receptors that may reflexly influence upper airway dilating muscle activity independently of pressure changes in awake normal humans.

Mechanical chest-wall vibration does not relieve air hunger.

Mechanical vibration of the chest wall can reduce dyspnea. It is unclear which sensations of respiratory discomfort are modulated by vibration (work/effort, air hunger, tightness). We performed two experiments to test whether vibration modifies air hunger: Experiment 1-eight adults performed six breath holds and rated their uncomfortable 'urge to breathe.' Vibration was applied separately at four chest-wall and two control sites, using two amplitudes. Breath-hold duration and ratings were unchanged by vibration at any site or amplitude. Experiment 2-nine adults were mechanically ventilated (mean 8.73 L/min) at constant hypercapnia (mean 48 mmHg) to produce mild to moderate ratings of air hunger (mean 37% of scale) with minimal respiratory muscle work. Vibration at 2nd or 3rd intercostal spaces during either inspiration or expiration did not change air hunger compared to triceps vibration. These experiments demonstrated that vibration does not relieve air hunger; we postulate that the effect of vibration is specific to the form of dyspnea.

The adult respiratory distress syndrome after dextran infusion as an antithrombotic agent in free TRAM flap breast reconstruction.

Adult respiratory distress syndrome occurred in a patient who had received dextran as a routine antithrombotic agent during and after free TRAM breast reconstruction. Although most patients who receive dextran have no adverse reaction, particularly after hapten inhibition by dextran 1 infusion, the serious nature of this complication in an elective operation calls into question the continuing routine use of dextran in microsurgery.

Respiratory sensations in asthma: physiological and clinical implications.

Dyspnea is a cardinal symptom of asthma and may arise from several pathophysiological mechanisms, including pulmonary hyperinflation, stimulation of vagal receptors, and, rarely, chemoreceptor stimulation. The language that patients use to describe their breathlessness may provide important clues about the physiology underlying symptoms in a particular patient. Several physiological derangements may contribute to dyspnea in a given individual. The variability in the severity of breathlessness for any given degree of airflow obstruction may relate to differences in the relative importance of these physiological changes and/or to a range of perceptual abilities in asthmatic patients. One hypothesis that is under current investigation is that defective perception of asthma symptoms may lead to undertreatment and the potential for greater morbidity and mortality from asthma.

Effect of chest wall vibration on dyspnea during hypercapnia and exercise in chronic obstructive pulmonary disease.

Vibration of chest wall inspiratory muscles during inspiration (in-phase) reduces breathlessness associated with hypercapnia and resistive loading in normal subjects and in patients with chronic obstructive pulmonary disease (COPD) at rest. To evaluate further the effect of chest wall vibration on breathlessness ("breathing discomfort") in patients, we studied 10 subjects 52 to 79 yr of age with severe dyspnea (mean FEV1, 0.75 L, 27% predicted). On a single day, we used two separate stimuli to produce mild to moderate breathlessness (BR): Protocol 1, steady-state hypercapnia; Protocol 2, exercise with a lower extremity ergometer. During each protocol, we applied in-phase chest wall vibration (CW) randomly alternating with one of two controls: deltoid vibration (DV) or no vibration (NV). During hypercapnia, CW significantly reduced BR (DV, 2.9 +/- 2.1; CW, 2.3 +/- 1.4; p < 0.05; NV, 3.3 +/- 2.1; CW, 2.6 +/- 2.0; p < 0.01) without significant changes in ventilation. During exercise, CW did not significantly alter BR relative to controls. These findings may be explained by the effect of vibration on the sense of respiratory effort and/or by improvement of the match between efferent motor commands and afferent information from the respiratory system. The lack of effect during exercise on BR suggests there may be a "therapeutic window" or range of conditions within which CW is effective in reducing dyspnea in patients with COPD.

Phasic electromyographic activity of the genioglossus increases in normals during slow-wave sleep.

Obstructive apneas occur infrequently during Stage 3-4 NREM sleep (SWS), even in patients with severe obstructive sleep apnea. To investigate whether upper airway (UA) dilator muscle activity preferentially increases during SWS as a partial explanation for this phenomenon, we measured phasic electromyogram activity of the genioglossus muscle (EMGgg) during continuous Stage 2 NREM sleep and SWS in 5 healthy males. Subjects were studied supine during a complete cycle of nocturnal NREM sleep after partial sleep deprivation. EMGgg was measured with perorally inserted bipolar electrodes, and quantified as peak phasic inspiratory activity during all continuous epochs of NREM sleep. We found EMGgg to be increased during SWS relative to stage 2 sleep by a mean of 58% among all subjects (P = 0.02); neither end-tidal PCO2 nor inspired minute ventilation varied between these sleep stages. Upper airway resistance, measured in 3 of the subjects on a separate study night, was not different between SWS and Stage 2 sleep. We speculate that the increase in phasic EMGgg during SWS in our normal subjects may reflect a mechanism whereby UA patency tends to be preserved during this stage.

Oscillation of the lung by chest-wall vibration.

Vibration of the thoracic surface has been shown to modify the drive to breathe and the sensation of dyspnea. It has been suggested that respiratory muscle afferents generate these effects. The possibility that the consequences of chest-wall vibration also involve intra-pulmonary afferents led us to investigate whether such vibration reaches the airways. Two vibratory stimuli were independently applied to four chest-wall sites and two control sites on eight healthy subjects. During separate breath holds, the vibrator was held on each site while subjects periodically opened and closed the pharynx. Airway pressure (P(AW)) was measured at the mouth. Spectral analysis of P(AW) showed pressure oscillations occurred at the same frequency as that of the vibrators when the pharynx was open; oscillation amplitude was vastly reduced when the pharynx was closed. Oscillation amplitude was also significantly larger during vibration at greater amplitude. These data demonstrate that vibration over the chest-wall vibrates the lung and could potentially excite intrapulmonary receptors.

Airway effects of monosodium glutamate in subjects with chronic stable asthma.

We studied the effect of oral monosodium glutamate (MSG) on airways function in 12 subjects with a history of chronic stable asthma in a double-blind, randomized, crossover protocol. Subjects ingested either 25 mg/kg of MSG or sodium chloride (equimolar to MSG) following a 6-hour fast. Spirometry [forced expiratory volume in 1 second (FEV1) and forced vital capacity] was performed before administration of the test substances and for a minimum of 4 hours thereafter. At no time during the observation period was the mean change in FEV1 more negative following MGS than following placebo. MSG is unlikely to be a contributing factor in bouts of bronchospasm in subjects with asthma, and routine avoidance of MSG by individuals with asthma need not be advised.

Cold facial stimulation reduces breathlessness induced in normal subjects.

Patients with breathlessness commonly describe subjective relief when seated near an open window or in front of a fan. Previous studies suggest that a flow of air or application of cold solutions to the face, nasal mucosa, or pharynx may alter ventilation. We hypothesized that a flow of cold air directed against the cheek would reduce the sensation of breathlessness associated with loaded breathing. Sixteen subjects breathed on a device with an inspiratory resistive load (63 cm H2O/L/s) while PCO2 was maintained at 55 torr for 5 min. All studies were performed 4 times with each subject, twice with cold air directed against the cheek (4 degrees to 10 degrees C, 4 km/h) and twice with no flow on the subject. Subjects were asked to rate their breathlessness using a modified Borg scale. Cold air directed on the face reduced breathlessness induced by an inspiratory resistive load and hypercapnia (6.2 +/- 1.7 Borg scale units with no flow, 5.1 +/- 1.7 with cold air; p less than 0.002) without causing a significant reduction in ventilation. This effect was not observed when cold air was directed to the leg and does not appear to be associated with a reduction in the ventilatory response to hypercapnia or with initiation of the diving reflex. We conclude that cold air directed against the cheek significantly reduces dyspnea associated with the combination of hypercapnia and an inspiratory resistive load.

Breathlessness induced by dissociation between ventilation and chemical drive.

Suppression of ventilation by tasks such as talking may produce breathlessness in normal individuals under conditions when a strong respiratory drive exists, e.g., during exercise, and in patients with severe lung disease. To investigate the nature of breathlessness produced by a dissociation between ventilation and chemical drive, we studied ten naive normal subjects who breathed at various levels of ventilation while end-tidal PCO2 (PETCO2) was held at 55 mm Hg. After a 10-min equilibration period of free breathing at PETCO2 = 55 mm Hg, subjects used a visual target to adjust ventilation to five different levels ranging from 50% below to 50% above the chemically driven ventilation (CDV). Ratings of breathlessness were made on a visual analogue scale relative to the intensity of breathlessness experience at CDV. As ventilation was targeted to levels below CDV, all subjects became increasingly breathless; the response was more variable when ventilation was targeted to levels above CDV. Overall, the relationship between ventilation and breathlessness was described by a hyperbolic function, for which the coefficient of determination (R2) was 0.92. Ventilation was suppressed below CDV without recruitment of antagonistic muscles during inspiration. The intensity of breathlessness was not correlated with measures of respiratory effort. We conclude that suppressed ventilation is a useful model for the study of breathlessness not fully explained by measures of respiratory effort and we speculate that the dissociation between chemical drive and afferent signals produced by motion of the lung and chest wall is important in modulating the sensation of breathlessness.

Language of dyspnea in assessment of patients with acute asthma treated with nebulized albuterol.

To investigate whether the language of dyspnea provides relevant clinical information in addition to that provided by ratings of overall dyspnea intensity when assessing subjective response to therapy, we conducted a prospective study in a cohort of 25 patients with acute asthma presenting to the emergency department of a tertiary care hospital. Patients received nebulized albuterol treatments every 20 min with a maximum of three doses. At presentation and after each treatment, patients completed spirometry, rated overall dyspnea intensity on a modified Borg scale, and selected phrases that described qualities of breathlessness from a 15-item questionnaire. Paired Student's t tests revealed significant improvements in FEV1 (from 1.39 +/- 0.66 L to 1.80 +/- 0.76 L, p < 0. 001) and reductions in dyspnea intensity (from 5.12 +/- 2.08 to 2.82 +/- 1.59, p < 0.001) after the first albuterol treatment. Dyspnea intensity continued to decrease significantly in response to the second treatment, modified Borg rating 2.26 +/- 1.52, although there was no positive bronchodilator response. The results from Cochran Q tests revealed that the frequency of the experience of "chest tightness" decreased significantly across the phases of treatment. However, the sensations of "work" or "breathing effort" persisted at the same time that the FEV1 revealed ongoing airways obstruction. We conclude that attention to the language of dyspnea would alert health care providers to residual air flow obstruction despite decreases in overall dyspnea intensity.

Dyspnea: a sensory experience.

Dyspnea--an unpleasant or uncomfortable awareness of breathing or need to breathe--is a common symptom of patients with cardiopulmonary disease. Although often thought of as a single symptom, dyspnea probably subsumes many sensations. Experimental conditions used to induce dyspnea are characterized by discrete groups or clusters of descriptive phrases. Similarly, as the language of dyspnea is refined further, different disease states may be distinguishable by the nuances of breathlessness described by patients. Evidence is gathering that the sensations of dyspnea are modified by information from a variety of receptors throughout the respiratory system. The sense of effort, although still important in the breathlessness associated with mechanical loads, is insufficient to explain the dyspnea arising from a number of experimental and clinical conditions. As our understanding of the interactions between effort and afferent information from the respiratory system grows, new therapeutic interventions to alleviate dyspnea are likely to follow.

Quality of dyspnea in bronchoconstriction differs from external resistive loads.

To test the hypothesis that patients perceive the same quality of dyspnea during mild bronchoconstriction and external resistive loads, we studied subjects with asthma under two conditions: (1) during methacholine bronchoprovocation to mimic the bronchospasm of mild asthma and (2) while breathing on a circuit to which was added a range of external resistors to mimic the mechanical load of mild asthma. During each of these stimuli, respiratory variables, overall dyspnea intensity on a modified Borg scale, and the qualitative descriptors of breathlessness from a 19-item questionnaire were assessed. The "chest tightness" and "constriction" responses were significantly more frequent in the methacholine trials as compared with the external load trials (p < 0.0001). The "chest tightness" or "constriction" response was chosen during 92% of the 26 trials of methacholine bronchoconstriction compared with 3% of the 72 trials of breathing against the external resistors. Changes in functional residual capacity were not significantly different between the two conditions. We conclude that in mild asthma, the sensation of chest tightness is distinct from the sensation of work and effort and is not attributable to the mechanical load imposed on the respiratory system.