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The segmentum accelerans in geese is a constriction in the caudal end of the primary bronchus. Experimental evidence suggests that this part of the airway functions as an inspiratory aerodynamic valve, accelerating the incoming airstream past the ventrobronchial openings. The luminal diameter of the segmentum accelerans dilates in the presence of elevated CO2 levels, probably through relaxation of smooth muscle. Physiological control of the segmentum accelerans may permit inspiratory aerodynamic valving to be maintained throughout a wide range of ventilatory flows.

The pectoral muscles in birds comprise up to a third of the body weight and provide the principal drive to the wing. Their attachment to the sternum suggests that they could compress the thorax and assist ventilation during flight. Most, but not all, birds have an integer ratio relationship between wingbeat and breathing frequency, but no measurements of the respiratory flow associated with the act of wingbeat are available. We recorded respiratory flow and wing timing in three starlings that flew at 22 knots (11 m·s −1 ) for up to 5 min in a wind tunnel. Triggering on wingbeat, we ensemble averaged flow records for many wingbeats in each flight. Because wingbeats occured throughout the respiratory cycle, breathing flow tended to average to zero, and a small flow event related to wingbeat emerged. The volume change associated with wingbeat ranged from 3 to 11% of tidal volume, and this is probably an overestimate. We conclude that wingbeat and breathing in starlings are essentially mechanically independent, despite the direct attachment of the locomotor muscles to the thorax.

To discuss the pathophysiology of dyspnea as it relates to patients suffering with chronic respiratory illness or end-stage disease.There are several publications highlighting important new concepts in this field including a new multidimensional model of dyspnea, similar to that developed for pain, that sheds new insight into the pathophysiology. Research in pulmonary rehabilitation, exercise testing and distractive auditory stimulation has also contributed to our understanding. Finally, there are new data on the emotional response of laboratory-induced dyspnea.Dyspnea is a complex symptom widely prevalent in advanced disease that involves multiple causes and pathophysiologies. The sensation of dyspnea is subjective and often evokes discomfort, fear, and anxiety. We recommend that this symptom be evaluated whenever vital signs are taken.

Inspiratory airflow in the avian lung completely bypasses the most cranial secondary bronchi (the ventrobronchi), and instead enters bronchi arising more caudally (the dorsobronchi). Dotterweich (1936) proposed that ‘aerodynamic valves’ prevented entry into the ventrobronchi. We have recently provided evidence that inspiratory aerodynamic valving in avian lungs depends on convective inertia in the primary bronchus (Banzett et al., 1987). Theoretical and physical models (Butler et al., 1988; Wang et al., 1988) showed that convective inertia could effect valving, but the effectiveness of valving at resting flows was less than that observed in the bird. This leads us to hypothesize that a segment of the primary bronchus is constricted, accelerating the gas and enhancing the convective inertia. To test this hypothesis in the present work we measured pressures throughout the airways and air sacs in anesthetized, pump-ventilated geese at different flow rates and gas densities. Our data show: (1) there is a large pressure drop in the primary bronchus close to the ventrobronchial junction, indicating the presence of a constriction; (2) this pressure drop increases with gas density and flow; (3) the convective inertia at this site is more than 10 times downstream opposing pressures. We conclude that the primary bronchus just cranial to the first ventrobronchus forms a constriction which accelerates inspired air. Furthermore, we conclude that the convective inertia of gas leaving this segment is sufficient to achieve inspiratory valving.

Although dyspnea is a common and troubling symptom, our understanding of the neurophysiology of dyspnea is woefully incomplete. Most measurements of dyspnea treat it as a single entity. Although the multidimensional dyspnea concept has been mentioned for many decades, only recently has the concept been the subject of experimental tests. Emerging evidence has begun to favor the hypothesis that dyspnea comprises multiple dimensions or components that can be measured as different entities. Most recently, studies have begun to show that there is a separable ‘affective dimension’ (i.e., unpleasantness and emotional impact). Understanding of the multidimensional measurement of pain is far in advance of dyspnea, and has enabled progress in the neurophysiology of pain, including identification of separate neural structures subserving various elements of pain perception. We propose here a multidimensional model of dyspnea based on a state-of-the-art pain model, and review existing evidence in the light of this model.

Ten men with cervical spinal cord injury were studied using magnetometers to record surface motions of the chest wall during speech breathing. Individual speech breathing patterns reflected inspiratory and expiratory muscular sparing. Subjects compensated for expiratory muscle impairment by speaking at large lung volumes, presumably to take advantage of the higher recoil pressures available at those volumes. Similarly, subjects used larger lung volumes to increase loudness. Abnormal chest wall behavior was attributed in large part to loss of abdominal muscle function. Because of this, speech breathing in individuals with cervical spinal cord injury may be improved by the use of abdominal binders.

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.

Hypoxia increases cerebral blood flow (CBF), but it is unknown whether this increase is uniform across all brain regions. We used H215O positron emission tomography imaging to measure absolute blood flow in 50 regions of interest across the human brain ( n = 5) during normoxia and moderate hypoxia. Pco2 was kept constant (∼44 Torr) throughout the study to avoid decreases in CBF associated with the hypocapnia that normally occurs with hypoxia. Breathing was controlled by mechanical ventilation. During hypoxia (inspired Po2 = 70 Torr), mean end-tidal Po2 fell to 45 ± 6.3 Torr (means ± SD). Mean global CBF increased from normoxic levels of 0.39 ± 0.13 to 0.45 ± 0.13 ml/g during hypoxia. Increases in regional CBF were not uniform and ranged from 9.9 ± 8.6% in the occipital lobe to 28.9 ± 10.3% in the nucleus accumbens. Regions of interest that were better perfused during normoxia generally showed a greater regional CBF response. Phylogenetically older regions of the brain tended to show larger vascular responses to hypoxia than evolutionary younger regions, e.g., the putamen, brain stem, thalamus, caudate nucleus, nucleus accumbens, and pallidum received greater than average increases in blood flow, while cortical regions generally received below average increases. The heterogeneous blood flow distribution during hypoxia may serve to protect regions of the brain with essential homeostatic roles. This may be relevant to conditions such as altitude, breath-hold diving, and obstructive sleep apnea, and may have implications for functional brain imaging studies that involve hypoxia.

The three common symptoms, pain, dyspnoea and cough, share some important features. We felt that the analogies to be made among them could be instructive, possibly suggesting new avenues of research. Each of these symptoms can be profoundly uncomfortable, and can profoundly degrade quality of life. The sign, cough, is often given more prominence than the symptom, urge to cough, but both are important to the patient (the former may be of more concern to nearby people). Advances in pain research over the last several decades have pointed the way to new studies of dyspnoea; they may serve as a model for the psychophysical study of the perception of urge to cough, as well as providing models for understanding both central and peripheral sensitization of the afferent pathway. We briefly review here the afferent and central pathways and psychophysics of pain, dyspnoea and urge to cough.

Recent evidence suggests that inhaled furosemide relieves dyspnoea in patients and in normal subjects made dyspnoeic by external resistive loads combined with added dead-space. Furosemide sensitises lung inflation receptors in rats, and lung inflation reduces air hunger in humans. We therefore hypothesised that inhaled furosemide acts on the air hunger component of dyspnoea. Ten subjects inhaled aerosolized furosemide (40 mg) or placebo in randomised, double blind, crossover experiments. Air hunger was induced by hypercapnia (50 ± 2 mmHg) during constrained ventilation (8 ± 0.9 L/min) before and after treatment, and rated by subjects using a 100 mm visual analogue scale. Subjects described a sensation of air hunger with little or no work/effort of breathing. Hypercapnia generated less air hunger in the first trial at 23 ± 3 min after start of furosemide treatment (58 ± 11% to 39 ± 14% full scale); the effect varied substantially among subjects. The mean treatment effect, accounting for placebo, was 13% of full scale ( P = 0.052). We conclude that 40 mg of inhaled furosemide partially relieves air hunger within 1 h and is accompanied by substantial diuresis.

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 Pco2 = 37 ± 2 Torr; end-tidal Po2 = 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 ( r2 = 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 ∼30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

Different views exist regarding sites within the brain responsible for eupneic respiratory rhythmogenesis. Studies by Lumsden in the 1920’s1,2 indicated that the minimum neural substrate for respiratory rhythm was the medulla but an intact pons was necessary for eupneic rhythm. Recent studies by St. John et al.3, 4 support this concept. Another concept is that the pre-Botzinger Complex (PBC) is the site of rhythmogenesis, and in the neonatal rat spinal cord-brainstem preparation, the minimum neural substrate for respiratory rhythm is the PBC.5 Another study on awake adult rats showed that greater than 80% destruction of PBC neurons expressing the neurokinin 1 receptor (NK1-R) resulted in an “ataxic” breathing pattern and attenuation of eupneic breathing and CO2 sensitivity, leading to the conclusion that “normal breathing in an intact animal requires an intact PBC”.6 However, St. John et al4 contend that an ataxic breathing pattern is evident with lesions at other medullary sites, and we7 found that lesions in rostral medullary nuclei result in transient interruptions of eupneic breathing. In addition, pre-inspiratory neurons rostral to the PBC are capable of generating a respiratory rhythm.8, 9

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.

We previously used a verbal ordinal rating scale to measure dyspnea. That scale was easy for subjects to use and the words provided consistency in ratings. We have recently developed a word labeled visual analog scale (LVAS) with labels placed by the subjects, retaining the advantages of a verbal scale while offering a continuous scale that generates parametric data. In a retrospective meta-analysis of data from 43 subjects, individuals differed little in their placement of words on the 100 mm LVAS (mean+/-S.D. for slight=20+/-2.5 mm, moderate=50+/-5 mm and severe=80+/-6 mm) and ratings were distributed uniformly along the scale. A significant stimulus-response correlation was obtained for both the LVAS (r(2)=0.98) and for the verbal ordinal scale (Spearman r=0.94). The resolution of the two scales differed only slightly. With meaningful verbal anchors, well-defined end-points, and clear instructions about the specific sensation to be rated, both scales provide valid measures of dyspnea.

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 O2 curves rose sharply at Pet O2 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.

Asthma evokes several uncomfortable sensations including increased "effort to breathe" and chest "tightness." We have tested the hypotheses that "effort" and "tightness" are due to perception of increased work performed by the respiratory muscles. Bronchoconstriction was induced by inhaled methacholine in 15 subjects with mild asthma (FEV(1)/FVC baseline = 81.9% +/- 5.8; bronchoconstriction = 64.0% +/- 8.6). To relieve the work of breathing, and thereby minimize activation of respiratory muscle afferents and motor command, subjects were mechanically ventilated. Subjects separately rated effort to breathe and tightness during mechanical ventilation and during spontaneous breathing. Bronchoconstriction produced elevated end-expiratory lung volume (279 +/- 62 ml); in a control study, end-expiratory lung volume was increased equally in the absence of bronchoconstriction by increasing end-expiratory pressure. During bronchoconstriction, ratings of effort were greater during spontaneous breathing than during mechanical ventilation (p < 0.05). Ratings of tightness were unchanged by the absence of respiratory muscle activity (p = 0.12). Hyperinflation alone did not produce tightness or effort. We conclude that tightness is not related to the increase in respiratory work during bronchoconstriction.

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.

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.

The device described in this study uses functionally variable dead space to keep effective alveolar ventilation constant. It is capable of maintaining end-tidal[Formula: see text] and[Formula: see text] within ±1 Torr of the set value in the face of increases in breathing above the baseline level. The set level of end-tidal [Formula: see text] or[Formula: see text] 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.

Dyspnea (shortness of breath) and pain are well-evolved warnings of important physiological derangements that may require animals to alter their behavior to survive. Dyspnea and pain are also two of the most common symptoms that bring patients to medical care, another potentially adaptive behavior.

Background Laboratory-induced dyspnea (breathing discomfort) in healthy subjects is widely used to study perceptual mechanisms, yet the relationship between laboratory-induced dyspnea in healthy volunteers and spontaneous dyspnea in patients with chronic lung disease is not well established. We compared affective responses to dyspnea 1) in COPD patients vs. healthy volunteers (HV) undergoing the same laboratory stimulus; 2) in COPD during laboratory dyspnea vs. during activities of daily living (ADL). Methods We induced moderate and high dyspnea levels in 13 COPD patients and 12 HV by increasing end-tidal CO2 (PETCO2) during restricted ventilation, evoking air hunger. We used the multidimensional dyspnea profile (MDP) to measure intensity of sensory qualities (e.g., air hunger (AH) and work/effort (W/E)) as well as immediate discomfort (A1) and secondary emotions (A2). Ten of the COPD subjects also completed the MDP outside the laboratory following dyspnea evoked by ADL. Results COPD patients and HV reported similar levels of immediate discomfort relative to sensory intensity. COPD patients and HV reported anxiety and frustration during laboratory-induced dyspnea; variation among individuals far outweighed the small differences between subject groups. COPD patients reported similar intensities of sensory qualities, discomfort, and emotions during ADL vs. during moderate laboratory dyspnea. Patients with COPD described limiting ADL to avoid greater dyspnea. Conclusions In this pilot study, we found no evidence that a history of COPD alters the affective response to laboratory-induced dyspnea, and no difference in affective response between dyspnea evoked by this laboratory model and dyspnea evoked by ADL.

The time course of change in ‘air hunger’, the uncomfortable urge to breathe, was assessed following sudden increases and decreases in P et CO 2 . 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. P et CO 2 was changed by altering F i CO 2 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 P et CO 2 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.

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.

The unidirectional gas-flow pattern through the avian lung is thought to result from ‘aerodynamic valves’; support for this hypothesis lies mainly in the failure to find any evidence for anatomical valves. During expiration, air flows from the caudal air sacs through the major exchange area of the lung, the paleopulmonic parabronchi, instead of bypassing the lungs via the intrapulmonary bronchus. We tested whether the effectiveness of this expiratory flow control mechanism depends on aerodynamic factors, especially convective inertial forces that depend on gas density and flow velocity. In pump-ventilated, anaesthetized geese, a bolus of tracer gas was introduced into both the right and left caudal thoracic air sacs during an end-inspiratory pause. During the first expiration, the rise of tracer levels within the caudal trachea was measured. Valve efficacy was positively correlated with the AO rate of expiratory gas flow, (range 8–200 ml s-1). At flows assumed to occur during exercise in geese , the expiratory valve efficacy was approximately 95 %; it was less effective at lower flows. Surprisingly, the density (ρ) of the background gas (ρ of He/O2=0.43 g l-1, Ar/O2=1.72 g l-1 or SF6/O2=5.50 g l-1) had no effect on expiratory valving. We suggest two possible mechanisms that might explain this unusual combination of flow dependence without density dependence. (1) If airway geometry changes occurred between experiments with different gases, flow in the vicinity of the expiratory valve may have varied independently from flow measured at the airway opening. (2) Alternatively, valving may depend on dynamic compression of the intrapulmonary bronchus, which could depend mainly on viscous resistance and thus on flow velocity but not gas density.

This investigation provides the first detailed description of speech production during mechanical ventilation. Seven adults with tracheostomies served as subjects. Recordings were made of chest wall motions, neck muscle activity, tracheal pressure, air flow at the nose and mouth, estimated blood-gas levels, and the acoustic speech signal during performance of a variety of speech tasks. Results indicated that subjects spoke for short durations that spanned all phases of the ventilator cycle, altered laryngeal opposing pressures in response to the continually changing tracheal pressure wave, and expended relatively small volumes of gas for speech production. Speech was improved by making selected ventilator adjustments. Suggestions for clinical interventions are offered.

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.

Congenital central hypoventilation syndrome (CCHS) is associated with hypoventilation during sleep, but breathing can be adequate during wakefulness. It has been assumed that in awake CCHS patients breathing is activated by the forebrain, even voluntarily (i.e. Ondine's Curse). We tested whether or not an abnormal breathing pattern can be provoked by intense mental concentration in CCHS patients as this would be expected to disturb any voluntary control over breathing if present. Breathing (inductance plethysmography), end-tidal PCO2) (PETCO2), arterial oxygen saturation (SaO2) and EEG were measured in 5 children with CCHS (aged 8-17 years) and 5 controls during 5 min periods while resting; reading; performing mental arithmetic and playing a hand-held "Nintendo" game. There were no significant differences between controls and CCHS (unpaired t-tests, P > 0.05) in mean breath duration, tidal volume, ventilation, SaO2 or PETCO2 during REST or the conditions of mental stimulation. Both groups increased ventilation during mental stimulation. Respiratory variability was not greater in CCHS in any condition. These data provide indirect evidence that CCHS patients do not require voluntary activation of every breath (they do not have Ondine's Curse) and suggest that mental concentration might stimulate the respiratory complex as part of a generalised CNS arousal.

An urge to breath is perceived during breath hold and hypercapnia (termed 'air hunger') and during heavy exercise (often termed 'shortness of breath'). To better understand the neural mechanisms responsible for these sensations we studied five patients (8-17 years old) with congenital central hypoventilation syndrome (CCHS) who lack ventilatory response to CO2. CCHS patients reported no respiratory discomfort during CO2 inhalation or during maximal breath hold which was of much longer duration than age-matched controls. However, all 3 CCHS patients who exercised heavily reported some sensations akin to shortness of breath (they increased breathing nearly as much as controls). Our results are consistent with two possibilities. First, the air hunger of hypercapnia and breath hold is caused by projection to the forebrain of respiratory chemoreceptor afferents which bypass the respiratory centers, while exercise shortness of breath is caused by direct projections of limb afferents or locomotory center activity. Second, air hunger and shortness of breath share the same origin--projection of increased brain stem respiratory center motor activity (corollary discharge) to the forebrain.

1. In healthy humans during aerobic exercise ventilation increases and mean arterial PCO2 usually remains constant over a wide range of CO2 production. 2. Congenital central hypoventilation syndrome (CCHS) is associated with ineffective chemoreceptor regulation of breathing and severe hypoventilation during sleep (requiring mechanical ventilation) reflecting abnormalities in the brainstem respiratory complex or its chemoreceptor input. Such patients can have adequate spontaneous ventilation during resting wakefulness and participate in normal activities. 3. If children with CCHS have normal ventilatory responses to exercise then chemoreceptors are not necessary for this ventilatory response or the resultant control of Pa,CO2 during exercise. We studied five children with CCHS (aged 8-17 years) with abnormally low ventilatory responses to steady-state increased end-tidal PCO2 (< 9 ml min-1 kg-1 mmHg-1) and five age-matched controls. 4. Depth and rate of breathing, end-tidal PCO2, end-tidal PO2, CO2 production, O2 utilization and heart rate were monitored during the following conditions: whilst subjects stood at rest; following the onset of treadmill exercise (4 m.p.h.); during steady-state exercise (4 m.p.h.); during an incremental maximal exercise test; and during recovery from exercise. 5. There were no significant differences in the ventilatory responses between CCHS subjects and controls during the onset of treadmill exercise, in the dynamic response in achieving the steady-state exercise, during steady-state exercise, in the recovery from steady-state exercise, or during incremental exercise (up to the point of presumed blood lactate accumulation, as indicated by gas exchange criteria). There was a very small mean increase in PCO2 in both groups during steady-state exercise (controls 1.4 mmHg; CCHS 2.2 mmHg). 6. The only differences which emerged between groups were (i) slightly more variability in PCO2 in the CCHS group during steady-state exercise, and (ii) the CCHS subjects did not hyperventilate, as the controls did, at exercise levels above the point of presumed blood lactate accumulation. 7. Breath-by-breath coefficient of variation of ventilation was significantly reduced in both groups during steady-state exercise compared to rest. There were no differences between groups in either state. 8. We conclude that chemoreceptors are not necessary for an appropriate ventilatory response to aerobic exercise. Hence, other stimuli, such as afferent information from the exercising limbs or signals related to activation of the motor cortex, can increase alveolar ventilation in close proportion to CO2 production. 9. The lack of hyperventilatory response to blood lactate accumulation during heavy exercise provides good evidence that these CCHS patients have ineffective peripheral chemoreception.

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 (V T ) on CO 2 -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 P CO 2 was maintained at a constant but elevated level. V T was varied between the subjects' normal V T and a smaller V T . 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 V T was nearly identical to that previously experienced with CO 2 alone. We conclude that afferent information from the lungs and upper airways is sufficient to modify the sensation of air hunger.

It has been suggested that the act of taking a stride produces substantial respiratory volume displacement and that this assists the respiratory muscles during locomotion. We measured the flow at the mouth associated with stride in walking and running humans and found it to be 1–2% of respiratory tidal volume, which is too small to make an appreciable contribution to pulmonary ventilation.

Rahn et al. (J. Appl. Physiol. 69: 1546-1548, 1990) showed that the gas pressure in a plethysmograph containing an intact egg oscillates in phase with electrocardiogram (ECG) and that this pressure variation could be used as a noninvasive way to determine the heart rate of an avian embryo. One possible mechanism to account for the pressure oscillation is the mechanical movement of the embryonic heart, which leads to volume shifts of gas within the plethysmograph. Another possibility is that the oscillation of gas pressure with heartbeat is pulsatile gas exchange resulting from pulsatile blood flow. If gas exchange were transiently stopped, a pressure signal dependent on gas exchange should disappear, while a pressure signal dependent on cardiovascular motion should persist. Using a number of late-age hen eggs (at days 15-20 of incubation), we tested these hypotheses by suddenly changing the gas composition surrounding an egg and measuring the effect of the pressure oscillation. We found that 1) after 5% CO2-95% N2 was flushed into the plethysmograph (presumably halting gas exchange), pressure oscillations went almost to zero and the ECG signal remained; after air was flushed back to the plethysmograph, the pressure signal returned to control level; 2) after 20% CO2-20% O2-60% N2 was flushed into the plethysmograph (presumably increasing net gas exchange), the pressure signal increased 2.5-fold compared with that in air; and 3) after 1% CO2-99% N2 was flushed into the plethysmograph (presumably reversing gas exchange), the oscillation pressure decreased to one-fourth of that in air and the phase of pressure relative to ECG reversed compared with the phase in air.(ABSTRACT TRUNCATED AT 250 WORDS)

Inspiratory muscle activity increases when lung volume is increased by continuous positive-pressure breathing in conscious human subjects (Green et al., Respir. Physiol. 35: 283–300, 1978). Because end-tidal CO2 pressure (PETCO2) does not change, these increases have not been attributed to chemoreflexes. However, continuous positive-pressure breathing at 20 cmH2O influences the end-tidal to arterial CO2 pressure differences (Folkow and Pappenheimer, J. Appl. Physiol. 8: 102–110, 1955). We have compared PETCO2 with arterial CO2 pressure (PaCO2). We have compared PETCO2 with arterial CO2 pressure (PaCO2) in healthy human subjects exposed to continuous positive airway pressure (10 cmH2O) or continuous negative pressure around the torso (-15 cmH2O) sufficient to increase mean lung volume by about 650 ml. The difference between PETCO2 and PaCO2 was not decreased, and we conclude that PETCO2 is a valid measure of chemical drive to ventilation in such circumstances. We observed substantial increases in respiratory muscle electromyograms during pressure breathing as seen previously and conclude this response must originate by proprioception. On average, the compensation of tidal volume thus afforded was complete, but the wide variability of individual responses suggests that there was a large cerebral cortical component in the responses seen here.

Experiments were performed in anesthetized chickens in order to determine functional characteristics and localization of intrapulmonary chemoreceptors. Each lung of the bird was separately unidirectionally ventilated with controlled gas mixtures at controlled flow rates; pulmonary blood flow to one lung could be occluded. Action potentials in vagal afferents from the receptors as well as ventilatory responses to stimulation of the receptors were recorded. Main findings include: (a) Presence of two groups of afferent fibers carrying activity from intrapulmonary chemoreceptors, one in the vagus, the other in the cardiac sympathetic nerve, (b) Intrapulmonary chemoreceptors show high sensitivity to CO 2 concentration in lung gas and blood; they show little sensitivity to arterial pH, to most drugs which stimulate arterial chemoreceptors, to mild mechanical distortion of the lung, or to substances in bronchial arterial blood, (c) The receptors are located in the parabronchi. It is suggested that physiological processes monitored by intrapulmonary CO 2 receptors are those which modify parabronchial P CO 2 , i.e. ventilation, venous CO 2 load, and mixed venous P CO 2 .

We tested the response of nine barbiturate-anesthetized dogs to high-frequency ventilation (HFV) (40-55 ml tidal volumes at 15 Hz) while measuring and controlling lung volume and blood gases. When lung volume and PCO2 were held constant, six of the nine responded to HFV by lengthening expiration. In each of these six dogs the maximal response was apnea. The response was immediate. In submaximal responses only expiration was changed; inspiratory time and peak diaphragmatic electrical activity were unaffected. There was a variable effect on abdominal muscle activity. If mean expiratory lung volume was allowed to increase at the onset of HFV, the Hering-Breuer inflation reflex added to the response. The strength of the response depended on level of anesthesia and arterial PO2. Vagotomy abolished the response in all cases. We conclude that oscillation of the respiratory system reflexly prolongs expiration via mechanoreceptors, perhaps those in the lungs.

Avian intrapulmonary chemoreceptor activity is reduced by increasing airway P CO 2 from 0 to 60 torr. Using extracellular electrodes, we recorded discharge of individual intrapulmonary chemoreceptor cell bodies in the left nodose ganglion of the rooster ( Gallus domesticus ) during unidirectional ventilation of the lungs. All receptors recorded were in the left lung. To vary pulmonary arterial P CO 2 independently of ventilation, we ventilated the two lungs separately and supplied the left pulmonary circulation with systemic arterial blood. When the P CO 2 in the pulmonary arterial blood was increased, discharge frequency decreased in all 21 receptors studied. Sensitivity to pulmonary arterial P CO 2 was similar to sensitivity to airway P CO 2 . When P CO 2 of ventilatory gas was lower than that of pulmonary arterial blood, discharge frequency of the receptor increased when pulmonary blood flow was stopped. Discharge frequency also increased when P CO 2 at the receptor site was lowered by increased ventilatory gas flow. We conclude that intrapulmonary chemoreceptors respond to the delivery and removal of CO 2 by blood and ventilatory gas. This suggests that the receptors are located within the respiratory gas exchange region of the lung. Because these receptors have a strong inhibitory effect on ventilation, they may serve to (1) adjust minute ventilation to the rate of metabolic CO 2 production and (2) to regulate individual breath size.

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 ellevated 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.