Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

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.

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.

High strength stimulation of the vagus nerve in awake humans: a lack of cardiorespiratory effects.

UNLABELLED: Vagus nerve stimulation is used to reduce the frequency and intensity of seizures in patients with epilepsy. In the present study four such patients were studied while awake. We analyzed the physiological responses to vagus nerve stimulation over a broad range of tolerable stimulus parameters to identify vagal A-fiber threshold and to induce respiratory responses typical of C-fiber activation. A-fiber threshold was determined by increasing stimulation current until laryngeal motor A-fibers were excited (frequency=30 Hz). With A-fiber threshold established, C-fiber excitation was attempted with physiologically appropriate stimulus parameters (low frequency and high amplitude). RESULTS: A-fiber thresholds were established in all patients, threshold currents ranged between 0.5 and 1.5 mA. Stimulation at lower frequency (2-10 Hz) and higher amplitudes (2.75-3.75 mA) did not produce cardiorespiratory effects consistent with C-fiber activation. It is possible that such effects were not observed because vagal C-fibers were not excited, because C-fiber effects were masked by the 'wakeful drive' to breathe, or because epilepsy or the associated therapy had altered central processing of the vagal afferent inputs.

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.

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.

Breathlessness in humans activates insular cortex.

Dyspnea (shortness of breath, breathlessness) is a major and disabling symptom of heart and lung disease. The representation of dyspnea in the cerebral cortex is unknown. In the first study designed to explore the central neural structures underlying perception of dyspnea, we evoked the perception of severe 'air hunger' in healthy subjects by restraining ventilation below spontaneous levels while holding arterial oxygen and carbon dioxide levels constant. PET revealed that air hunger activated the insular cortex. The insula is a limbic structure also activated by visceral stimuli, temperature, taste, nausea and pain. Like dyspnea, such perceptions underlie behaviors essential to homeostasis and survival.

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.

Simple contrivance "clamps" end-tidal PCO(2) and PO(2) despite rapid changes in ventilation.

The device described in this study uses functionally variable dead space to keep effective alveolar ventilation constant. It is capable of maintaining end-tidal PCO(2) and PO(2) within +/-1 Torr of the set value in the face of increases in breathing above the baseline level. The set level of end-tidal PCO(2) or PO(2) can be independently varied by altering the concentration in fresh gas flow. The device comprises a tee at the mouthpiece, with one inlet providing a limited supply of fresh gas flow and the other providing reinspired alveolar gas when ventilation exceeds fresh gas flow. Because the device does not depend on measurement and correction of end-tidal or arterial gas levels, the response of the device is essentially instantaneous, avoiding the instability of negative feedback systems having significant delay. This contrivance provides a simple means of holding arterial blood gases constant in the face of spontaneous changes in breathing (above a minimum alveolar ventilation), which is useful in respiratory experiments, as well as in functional brain imaging where blood gas changes can confound interpretation by influencing cerebral blood flow.

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.

Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity.

Breathlessness arises from increased medullary respiratory center activity projecting to the forebrain (respiratory corollary discharge hypothesis). Subjects with congenital central hypoventilation syndrome (CCHS) lack the normal hyperpnea and breathlessness during hypercapnia. The corollary discharge hypothesis predicts that if CCHS subjects have normal hyperpnea during exercise, they will experience normal breathlessness during exercise. To test this, we studied four CCHS subjects and six matched controls during an exhausting constant-load cycling test requiring substantial anaerobiosis. CCHS subjects rated significantly less breathlessness at the end of the test than controls, but ventilation (index of respiratory corollary discharge) was also somewhat lower in CCHS (not significant). In both groups, breathlessness increased disproportionately more than ventilation towards the end of exercise. These data failed to disprove the corollary discharge hypothesis of breathlessness, but do suggest that the relationship between ventilation and breathlessness is non-linear and/or that projections of chemoreceptor afferents to the forebrain (presumed lacking in CCHS) is one source of breathlessness in normals.

Competition between gas exchange and speech production in ventilated subjects.

Competition between airflow requirements for speaking and gas exchange occurs in ventilator-dependent tracheotomized subjects who can 'steal' air from alveolar ventilation during the ventilator's inflation phase to produce sound. We wondered whether these subjects adopted strategies to minimize hypoventilation when speaking, particularly when ventilatory drive and respiratory discomfort are increased by hypercapnia. We recorded speech and ventilatory and speaking volumes in five ventilated subjects during reading and extemporaneous speech. All subjects spoke during the ventilator's inflation (and expiratory) phase, losing approximately 15% of their inspired tidal volume. During induced hypercapnia (15 mmHg increase in PetCO2) which caused shortness of breath, all subjects could still speak adequately. Two subjects 'adapted' to hypercapnia by reducing the air used for speaking during inflation. In contrast, one subject reacted, as normal subjects do, by increasing the airflow per syllable (a mal-adaptive strategy in ventilated subjects). These changes were modest despite the strong hypercapnic stimulus.

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.

Self-control and external control of mechanical ventilation give equal air hunger relief.

Elevated end-tidal partial pressure of CO2 (PET(CO2)) causes air hunger; this sensation becomes intense with a relatively small rise in PET(CO2) if ventilation is held constant. Spontaneously breathing subjects increase ventilation in response to CO2, thereby greatly diminishing air hunger. In healthy subjects and ventilator-dependent patients, experimenter-induced increases in ventilator tidal volume (VT) relieve air hunger even if PET(CO2) is kept elevated. We addressed two questions: (1) Can paralyzed, ventilator-dependent patients use the sensation of air hunger to effectively control ventilator VT using nonrespiratory motor pathways; and (2) Do subjects obtain more relief when in control of their own ventilator? Four subjects were trained to increase ventilator VT using a mouth-operated switch. Subjects' ratings of air hunger intensity in response to elevated PET(CO2) were compared during three conditions: (1) constant VT; (2) subject-controlled VT; and (3) experimenter-controlled VT. When given control of their ventilator, all subjects increased VT in response to increased PET(CO2), thereby relieving air hunger. Air hunger relief was similar when the experimenter mimicked these VT changes. These results suggest that: (1) ventilator-dependent patients can use sensation, conscious decisions, and nonrespiratory motor pathways to achieve an appropriate respiratory response to increased PCO2 and (2) control of one's own ventilation is unimportant in these circumstances.

Perception of inflation of a single lung lobe in humans.

We tested whether subjects could detect and localize inflation confined to a single lung lobe. A balloon-sealed catheter was placed into a lobar bronchus of unsedated subjects via fiberoptic bronchoscopy. Topical anesthesia (lidocaine) was used to suppress cough and irritation associated with inflation of the sealing balloon. Small (45-60 ml) or large (100-240 ml) stimulus volumes were insufflated via the catheter. In a forced-choice protocol, subjects were readily able to detect large inflations and correctly identify the side on which the stimulus was given, but small inflations were at the threshold of detection and were not correctly localized. Additional lidocaine applied to the bronchus in two subjects did not degrade detection. Circumstantial evidence suggests that the sensation arose in the lung. We conclude that this technique is feasible for the study of pulmonary perception.

Dynamic response characteristics of CO2-induced air hunger.

The time course of change in 'air hunger', the uncomfortable urge to breathe, was assessed following sudden increases and decreases in PETCO2. Healthy normal men and women were mechanically ventilated at constant tidal volume and frequency, and were required to rate the perceived intensity of air hunger every 10-15 sec. PETCO2 was changed by altering FICO2 unbeknownst to the subject. Air hunger changed to its new level following steps with a median time constant of about 50 sec during hyperoxia. Changes in air hunger following PETCO2 steps were slightly faster when background gas was slightly hypoxic. Although the present results are consistent with the hypothesis that air hunger and ventilatory drive share the same receptors and central neural processes, analysis of dynamic response is probably not sensitive enough to disprove the hypothesis.

Air hunger induced by acute increase in PCO2 adapts to chronic elevation of PCO2 in ventilated humans.

Brief increases in arterial PCO2 (PaCO2) (lasting several minutes) produce a sensation of respiratory discomfort (air hunger). It is not known whether air hunger adapts to chronic changes in PaCO2. This study tested whether the level of end-tidal PCO2 (PETCO2) required to evoke air hunger would increase with chronic elevation of PETCO2 (lasting several days). Four ventilator-dependent subjects participated in a 2-wk study during which they were ventilated with air (placebo) or air rich in CO2 (CO2 exposure). Average resting PETCO2 during control periods was 25 Torr (typical for such patients); PETCO2 was 15 Torr higher during CO2 exposure. Ventilation and arterial PO2 did not differ between conditions. Periodically, we performed tests in which subjects rated the intensity of air hunger induced by brief increases in PETCO2. The increase in PETCO2 required to elicit a given air hunger rating during CO2 exposure also increased by approximately 15 Torr. That is, subjects' sensation of air hunger fully adapted to the chronic increase in PETCO2. Arterial pH did not fully return to control values during CO2 exposure. Accommodation in the chemoreceptors and neural pathways that subserve air hunger sensation may explain the adaptation of air hunger.

Ventilatory relief of the sensation of the urge to breathe in humans: are pulmonary receptors important?

1. The sensation of an urge to breathe (air hunger) associated with a fixed level of hypercapnia is reduced when ventilation increases. The aim of the present study was to investigate whether pulmonary receptors are important in this mechanism. 2. Five heart-lung transplant (HLT) subjects and five control subjects were studied during periods of mechanical and spontaneous ventilation. End-tidal Pco2 (PET,CO2) was increased by altering the level of inspired CO2. Throughout, subjects rated sensations of air hunger. Air hunger was also monitored during and immediately following maximal periods of breath-holding. 3. When the level of mechanical ventilation was fixed, both groups experienced a high degree of air hunger when PET,CO2 was increased by about 10 mmHg. At similar levels of hypercapnia, both groups derived relief from approximately twofold increases in tidal volume, although relief was slightly less effective in HLT subjects. This was reversible, with decreases in the level of mechanical ventilation rapidly giving rise to increased ratings of air hunger. 4. With breath-holding, all subjects obtained some respiratory relief within 2 s of the break point; there was no significant difference between the groups. 5. The results suggest that sensations of an urge to breathe induced by hypercapnia can be modulated by changes in tidal volume in the presumed absence of afferent information from the lung.

Self-control of level of mechanical ventilation to minimize CO2 induced air hunger.

Hypercapnia produces an uncomfortable urge to breathe ('air hunger'), which is alleviated by increasing breathing. It has been postulated that awake humans control breathing partly to minimize these sensations; such behavioral control presumably involves the forebrain. To test this postulate, we compared the ventilatory response to hypercapnia when the subject breathed spontaneously to the response when the subject used forebrain commands to control ventilation--on the basis of minimizing air hunger (achieved with subject-controlled positive pressure ventilation). In six healthy adults during hypercapnia (46 mmHg), spontaneous ventilation significantly exceeded, by 17%, the level of (mechanical) ventilation needed to alleviate air hunger. This suggests that spontaneous breathing is not behaviorally controlled to minimize discomfort. Alternatively, mechanical ventilation confers an additional relief of air hunger beyond that provided by spontaneous breathing. Since mechanical ventilation (with reduced respiratory muscle contraction) was more effective than spontaneous breathing in relieving air hunger, our results also suggest afferents that signal the degree of respiratory muscle contraction do not contribute to air hunger relief.