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.

Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via "corollary discharge" to higher centers; absence of dyspnea during low inspired Po(2) may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po(2) = 60-40 Torr) and hypercapnic hyperoxia (end-tidal Pco(2) = 40-50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, "matched" by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. "Air hunger" was rated every 30 s on a visual analog scale. Air hunger-Pet(O(2)) curves rose sharply at Pet(O(2)) <50 Torr. Air hunger was not different between matched stimuli (P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.

The perception of respiratory work and effort can be independent of the perception of air hunger.

Dyspnea in patients could arise from both an urge to breathe and increased effort of breathing. Two qualitatively different sensations, "air hunger" and "respiratory work and effort," arising from different afferent sources are hypothesized. In the laboratory, breathing below the spontaneous level may produce an uncomfortable sensation of air hunger, and breathing above it a sensation of work or effort. Measurement of a single sensory dimension cannot distinguish these as separate sensations; we therefore measured two sensory dimensions and attempted to vary them independently. In five normal subjects we obtained simultaneous ratings of air hunger and of work and effort while independently varying PCO(2) or the level of targeted voluntary breathing. We found a difference in response to the two stimulus dimensions: air hunger ratings changed more steeply when PCO(2) was altered and ventilation was constant; work or effort ratings changed more steeply when ventilation was altered and PCO(2) was constant. We conclude that "air hunger" is qualitatively different from "work and effort" and arises from different afferent sources.

Acute partial paralysis alters perceptions of air hunger, work and effort at constant P(CO(2)) and V(E).

Breathing sensations of AIR HUNGER, WORK and EFFORT may depend on projections of central motor discharge (corollary discharge) to the forebrain. Source of motor drive (brainstem or cortex) may determine what is perceived. To test the effect of changing motor discharge at constant ventilation, we induced partial neuromuscular blockade during hypercapnic hyperpnea (31 + or - 9 L min(-1); PET(CO(2))=49 + or - 2 Torr) and during matched volitional hyperpnea (34 + or - 5 L min(-1); PET(CO(2))=41 + or - 1 Torr). Decline of vital capacity was similar between conditions (39%). Ventilation was unchanged with paralysis, indicating increased respiratory motor drive to maintain hyperpnea. Sensations were rated on a seven point ordinal scale. Median EFFORT and WORK increased 3-3.5 points with paralysis during both forms of hyperpnea (P<0.02, Wilcoxon signed rank). Median AIR HUNGER increased 2.5 points with paralysis during hypercapnic (P<0.02) but not during volitional hyperpnea. Data suggests that EFFORT and WORK arise from motor cortex activity (subjects reported engaging volitional control when paralyzed even during hypercapnia) and suggests that AIR HUNGER arises from medullary motor activity.

Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy.

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.

Tidal volume perception in a C1-C2 tetraplegic subject is blocked by airway anesthesia.

We administered lidocaine aerosol intratracheal anesthesia to a ventilator-dependent, tracheostomized C1-C2 tetraplegic subject to determine its effect on her ability to detect small changes in tidal volume. A psychophysical test of volume detection was given before and immediately after a 20 percent lidocaine aerosol was delivered through the subject's cuffed tracheostomy tube. On each of three occasions, she reliably (p < .001) detected changes in tidal volume during a control period; on two of these occasions she could not detect the same volume after inhaling the anesthetic. On one occasion the anesthetic had no effect on volume perception, possibly because copious airway secretions interfered with lidocaine uptake. Subject-blinded control tests with saline aerosol inhalation did not affect detection. We concluded that this subject's tidal volume perception depended on mechanoreceptors in the lungs and thoracic airways and that local anesthetic interrupted these sensory signals when airway secretions were not excessive.

Stimulus-response characteristics of CO2-induced air hunger in normal subjects.

Hypercapnia evokes an uncomfortable sensation, termed 'air hunger'. We examined the relationship between PETCO2 and ratings of air hunger intensity under three conditions in 16 subjects: 1) mechanical ventilation with hyperoxic gas mixtures at fixed frequency and tidal volume (twice resting ventilation), 2) the same mechanical ventilation, but with hypoxic gas mixture, 3) spontaneous breathing with hyperoxic gas mixture. In each case, PETCO2 was varied randomly among several levels, each held for 5 min. During hyperoxic mechanical ventilation, the mean threshold for air hunger sensation was 43 Torr, i.e., 4 Torr above resting PETCO2; intolerable air hunger was evoked by 50 Torr. The threshold and tolerable levels of PETCO2 varied among individuals, but were not well correlated with their ventilatory responses to CO2. Hypoxia (PETO2 60-75 Torr) shifted the PETCO2 at both threshold and tolerance down by only 2 Torr. Breathing greatly reduced the air hunger experienced at any given PETCO2 (threshold increased 5 Torr, and sensitivity decreased 50%).

Neural drive to nasal dilator muscles: influence of exercise intensity and oronasal flow partitioning.

Our aim was to test the following hypotheses: 1) neural drive to the muscles of the alae nasi (AN) is proportional to nasal airflow and is independent of the overall level of central respiratory drive, and 2) the switch from nasal to oronasal breathing corresponds to the onset of marked flow turbulence in the nasal airway. Total and nasal inspired ventilation rates (VI) and the electromyogram (EMG) of the AN muscles were measured in seven subjects during progressive-intensity bicycling exercise. In separate experiments in six subjects the nasal VI corresponding to the transition from laminar to turbulent airflow was determined by measuring the pressure-flow relationship of the nasal airway with anterior rhinomanometry. Nasal VI accounted for 70 +/- 11% of total VI at rest and 27 +/- 8% (SE) at 90% of the maximal attainable power (max). Nasal VI and integrated AN EMG activities increased linearly with exercise intensity up to 60% of the max power, but both variables plateaued at this level even though total VI (and central respiratory drive) began to increase exponentially as exercise intensity increased to 90% max. The onset of the exponential rise in total VI was associated with a sharp increase in oral VI and with the onset of marked flow turbulence in the nasal airway. The results suggest that during incremental exercise 1) changes in AN EMG activities are highly correlated with changes in nasal VI, 2) turbulent flow in the nose may be the stimulus for the switch to oronasal breathing so that total pulmonary resistance is minimized, and 3) the correlation between nasal airflow and neural drive to the AN muscles is probably mediated by mechanisms that monitor airway resistance. Although these mechanisms were not identified, the most likely possibilities are receptors in the upper and/or lower airways that are sensitive to negative transmural pressure, or to effort sensations leading to greater corollary motor discharge to nasal dilator muscle motoneurons.

Imagination of dynamic exercise produced ventilatory responses which were more apparent in competitive sportsmen.

1. The cardiorespiratory response to imagination of previously performed treadmill exercise was measured in six competitive sportsmen and six non-athletic males. This was compared with the response to a control task (imaging letters) and a task not involving imagination ('treadmill sound only'). 2. In athletes, imagined exercise produced increases in ventilation which varied within and between subjects. The mean maximal increase (11.71 min-1) was approximately 20% of the ventilatory response to actual exercise. This was primarily due to treadmill speed-related increases in respiratory frequency (mean maximal increase, 14.8 breaths min-1) and resulted in significant reductions in end-tidal PCO2 (mean maximal fall, 7 mmHg). These effects were greater (P < 0.01) than any observed during the control tasks. 3. Changes in heart rate (mean increase, 12 beats min-1) were not significantly different from those observed during the control tasks (P > 0.2). 4. In non-athletes, imagination of exercise produced no changes in cardiorespiratory variables. No significant differences were detected in subjective assessments of movement imagery ability between athletes and non-athletes (P = 0.17). 5. This study demonstrates that ventilatory effects, when observed, are specific to imagination of exercise. The greater likelihood of generating ventilatory responses in highly trained athletes, experienced in 'rhythmic' sports, may be related to awareness of breathing and its role in exercise imagination strategy. A volitional component of the response cannot be discounted.

What do fully paralyzed awake humans feel when they attempt to move?

Subjects are able to judge the strength of muscle contraction. In theory, the force of muscular exertion could be perceived either from mechanoreceptor afferents or from knowledge of central motor command (corollary discharge). Sensations of great effort or exerted force have been described by subjects when their limbs were weakened by fatigue or partial paralysis. This has been taken as evidence that effort sensations arise from central motor commands rather than from mechanoreceptor afferent signals produced by muscle contraction. To differentiate between these possibilities, we used neuromuscular block to completely paralyze four waking subjects and required them to attempt maximal contraction of inspiratory muscles and of hand muscles. They were questioned after recovery about what their sensations were when attempting these contractions. None described the sensations of exerted force, great effort, or heaviness, which would have been expected if motor commands alone were the source of these sensations. The contradiction between our findings and those previously reported suggests that the specific neural mechanisms for effort sensations must be reexamined.

The experience of complete neuromuscular blockade in awake humans.

STUDY OBJECTIVE: To describe the subjective experience and the physiologic effects of endotracheal intubation and complete neuromuscular block in unsedated humans. SETTING: Metropolitan V.A. Hospital. PATIENTS: 4 healthy, unsedated volunteers. INTERVENTIONS: Subjects' tracheas were intubated using topical anesthesia, then subjects were completely paralyzed with vecuronium and mechanically ventilated at various end-tidal partial pressure of carbon dioxide (PETCO2) levels, all without sedation. MEASUREMENTS AND MAIN RESULTS: Heart rate (HR), blood pressure, oxygen saturation by pulse oximeter (SpO2), and PETCO2 were measured. Subjects' verbatim descriptions of their experiences and answers to systematic questions were recorded after the experiments. All subjects reported that tracheal intubation was a very unpleasant experience. None of the subjects found paralysis itself to be distressing, and it did not affect mentation. Subjects felt breathless when PETCO2 was even slightly elevated. HR was increased by intubation, but not by paralysis. All subjects reported sore throat, muscle aches, fever, and fatigue lasting up to 24 hours after the experiment. One subject experienced nausea and vomiting. Another subject experienced a sore throat that persisted for weeks due to a vocal cord ulcer, which resolved spontaneously. All subjects' SpO2 levels after the experiment were below their pre-experiment baselines. CONCLUSIONS: Our findings suggest that paralysis of healthy, knowledgeable, and psychologically well-prepared subjects for experimental purposes is feasible but may result in unpleasant, self-limiting after effects. Further, we conclude that, in any case of awake paralysis, close attention should be paid to arterial PCO2, adequate sedation and analgesia, minimization of pain during procedures, psychological support, and maintenance of communication when possible.

Reduced tidal volume increases 'air hunger' at fixed PCO2 in ventilated quadriplegics.

The act of breathing diminishes the discomfort associated with hypercapnia and breath-holding. To investigate the mechanisms involved in this effect, we studied the effect of tidal volume (VT) on CO2-evoked air hunger in 5 high-level quadriplegic subjects whose ventilatory capacity was negligible, and who lacked sensory information from the chest wall. Subjects were ventilated at constant frequency with a hyperoxic gas mixture, and end-tidal PCO2 was maintained at a constant but elevated level. VT was varied between the subjects' normal VT and a smaller VT. Subjects used a category scale to rate their respiratory discomfort or 'air hunger' at 30-40 sec intervals. In 4 of 5 subjects there was a strong inverse relationship between breath size and air hunger ratings. The quality of the sensation associated with reduced VT was nearly identical to that previously experienced with CO2 alone. We conclude that afferent information from the lungs and upper airways is sufficient to modify the sensation of air hunger.

Recording single motor unit activity of human nasal muscles with surface electrodes: applications for respiration and speech.

A method is presented for recording nasal single motor unit (SMU) potentials from the skin surface using a 3-pole 'branched' bipolar electrode. Stable, high-quality recordings of single motor unit activity were obtained for up to 3 h. Branched electrode arrays were capable of locating an SMU's maximal voltage point within 5 mm. We examined nasal SMU discharge patterns in relation to respiration in 9 adult humans. The majority of SMUs which discharged during quiet breathing began firing late in expiration and ceased firing in mid-inspiration, other SMUs discharged only during expiration, and a few fired continually with frequency modulation during breath cycles. With increased ventilation, new SMUs were recruited, and previously active SMUs increased the frequency and duration of their discharge. We examined the discharge of 13 units (5 adults) which discharged during speech but were never active during quiet or moderately increased breathing. Some of these SMUs fired during production of nasal consonants, and others were active for articulations involving facial movements (bilabial stops, labio-dental fricatives, and vowels produced with lip movement). By providing information about motor neuron recruitment which cannot be obtained from gross EMG recordings, surface recording of unit potentials may be useful in studying the central nervous control of the nasal upper airway, face, and neck for respiration and speech.

Perceptual cues used to reproduce an inspired lung volume.

The perceptual cues used to reproduce a specific lung volume were studied in five healthy males. Performance was examined under three conditions that were designed progressively to remove the reliability of cues that a subject might use to duplicate a specific lung volume. As judged by the mean errors (disregarding the sign of the error) and constant errors (including the sign of the error), there were no significant differences in the accuracy with which subjects reproduced a standard volume, even when they were required to perform the reproductions at various inspiratory rates and starting volumes. The best performance was in the final experimental session in which the mean error for the group, all conditions combined, was 133 ml. There was a difference between conditions on the just-noticeable differences (a measure of variability including the sign of the error); subject performance was significantly more variable when the inspiratory flow rate was altered. The group mean error for the final session for just-noticeable differences was 93.3 ml. Our results indicate that a specific lung volume can be achieved using cues other than those associated with the movement made to attain that lung volume. The specific afferents that provided these cues are not known, but we propose that they uniquely signal static position.

'Air hunger' from increased PCO2 persists after complete neuromuscular block in humans.

The tolerance of totally curarized subjects for prolonged breath hold is viewed by many as evidence that respiratory muscle contraction is essential to generate the sensation of breathlessness. Although conflicting evidence exists, none of it was obtained during total neuromuscular block. We completely paralyzed four normal, unsedated subjects with vecuronium (a non-depolarizing neuromuscular blocker). Subjects were mechanically ventilated with hyperoxic gas mixtures at fixed rate and tidal volume. End-expiratory PCO2 (PETCO2) was varied surreptitiously by changing inspired PCO2. Subjects rated their respiratory discomfort or 'air hunger' every 45 sec. At low PETCO2 (median 35 Torr) they felt little or no air hunger. When PETCO2 was raised (median 44 Torr) all subjects reported severe air hunger. They had reported the same degree of air hunger at essentially the same PETCO2 before paralysis. When questioned afterwards all subjects said the sensation could be described by the terms 'air hunger', 'urge to breathe', and 'shortness of breath', and that is was like breath holding. They reported no fundamental difference in the sensation before and after paralysis. We conclude that respiratory muscle contraction is not important in the genesis of air hunger evoked by hypercapnia.

'Air hunger' arising from increased PCO2 in mechanically ventilated quadriplegics.

A number of investigators have proposed that the sense of respiratory discomfort accompanying hypercapnia depends on respiratory mechanoreceptors which inform the sensory cortex of reflex increases in breathing. To test this hypothesis, we studied subjects whose respiratory muscles were paralyzed, and who were thus unable to increase breathing in response to hypercapnia. We gradually elevated inspired PCO2 in four tracheostomized quadriplegic subjects supported by constant mechanical ventilation. These subjects reported sensations of 'air hunger' (e.g., "short of breath", "air-starved") when end-tidal PCO2 increased 10 Torr (mean) above their resting levels. In a second experiment we used the forced-choice technique to determine the ability of three of these subjects to detect repeated changes of end-tidal PCO2. Two detected 7 Torr changes, the third detected 11 Torr changes. These data suggest that changes in breathing are not necessary to evoke the sense of 'air hunger'. We conclude that the likely mechanisms are (1) projection of chemoreceptor afferent traffic to the sensory cortex, and (2) projection of corollary discharge from brainstem respiratory centers to the sensory cortex.

Abdominal muscle activity during speech production.

Abdominal muscle activity was investigated during resting tidal breathing and speech production in upright and supine body positions in five male and five female young adult subjects. Results showed that patterns of abdominal electromyographic (EMG) activity were highly dependent on body position. Data for resting tidal breathing resembled those of previous investigations and revealed one sex-related finding. Data for speech production indicated that the lateral region of the abdomen was highly active in the upright position and occasionally active in the supine position. In the upright position, lateral EMG levels during speech production were characterized by generally higher levels in the lower than upper lateral sites and were almost always higher than during resting tidal breathing. In the supine position, EMG levels during speech production occasionally exceeded those associated with resting tidal breathing but were substantially lower than those associated with upright speech production. Abdominal EMG activity was most prevalent during loud speech production and during speech produced at low lung volumes. Findings are discussed in relation to current knowledge of respiratory mechanics and neural control.

High-level quadriplegics perceive lung volume change.

We tested the ability of tracheostomized, high-level quadriplegics to detect changes in ventilator-delivered tidal volume. Single breaths larger or smaller than control breaths were delivered, and the subjects indicated which breath was altered in a forced-choice procedure that minimizes the effect of subject bias. Quadriplegic patients detected changes in tidal volume of as little as 100 ml. Their ability to detect changes was comparable to that of a group of normal subjects similarly tested. These quadriplegic patients had little or no somatic sensation below the neck, and airways above the tracheostomy were not exposed to the stimulus. The quadriplegics consistently and emphatically reported that the sensation used in volume discrimination arose within the chest.

Inspiratory muscle responses to airway occlusion during learned breathing movements.

Respiratory muscle responses to sudden obstruction of learned breathing movements were studied in seven normal adults. Subjects were trained to inspire at a constant rate (0.4 liters/s), or maintain a static inspiratory effort(-10 cmH2O). On each trial these efforts were loaded unpredictably by occluding the airway or applying an opposing negative pressure at the mouth. Surface EMGs were recorded from the neck, parasternal intercostal, pectoral, diaphragmatic, and abdominal muscles. The latency and pattern of the responses to occlusion or to negative pressure were obtained from 10-trial computer-averaged records. When subjects were trained to relax in response to loading, inhibitory responses (mean latency: 32 ms) were recorded from the neck (16 out of 21 10-trial averages), diaphragm (9 out of 21), and parasternal (3 out of 21) locations. Excitatory responses (mean latency: 69 ms) were also recorded from the neck (11 out of 21 10-trial averages), diaphragm (8 out of 21), and parasternal (1 out of 21) sites. These responses were also observed in many single trial records. When subjects were trained to make an additional inspiratory effort as quickly as possible after loading, the reaction was a high-amplitude EMG burst, sometimes preceded by a brief inhibitory response. The mean reaction times for the large bursts were: 70 ms for the neck, 86 ms for the diaphragm, and 91 ms for the parasternal intercostals. Latencies in the 60- to 70-ms range were found on many 10-trial averages. Because the latencies of the excitatory responses evoked when subjects were trained to relax in response to loading were similar to those of the EMG bursts recorded when subjects were trained to react quickly in response to loading, it is not possible to distinguish long-latency reflex and learned response components on the basis of latency alone. Previous work, which has assumed that responses in the 50- to 70-ms latency range must be reflexive rather than learned, may need to be reexamined.

Reflex compensation of voluntary inspiration when immersion changes diaphragm length.

When immersion alters inspiratory muscle operating lengths, spontaneously breathing humans maintain a constant tidal volume by reflex adjustment of inspiratory muscle activation (Reid et al. J. Appl. Physiol. 58: 1136-1142, 1985). We term this the operational length compensation reflex. The present experiment demonstrates that similar adjustments occur during voluntary respiratory maneuvers. Each of seven naive subjects sat in a tank with water at hip level. We trained them to reproduce an inspired volume (+/- 10%) at constant inspiratory duration. They received verbal feedback during training but not during the experiment. We measured surface electromyograms (EMGs) of diaphragm and intercostal muscles and tidal volume. After the subjects were trained, we made repeated measurements of 10 trained breaths with water at the hip and then again after raising water level to the xiphoid (which decreases lung volume and increases operating length of the diaphragm). In 30 of 42 trials there was a substantial fall in peak diaphragm EMG. In 10 trials this was sufficient to prevent any change in tidal volume. Inspiratory flow was more closely regulated than tidal volume. Subjects were not aware of making adjustments in drive.