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Aerosol furosemide may be an option to treat refractory dyspnea, though doses, methods of delivery, and outcomes have been variable. We hypothesized that controlled delivery of high dose aerosol furosemide would reduce variability of dyspnea relief in patients with underlying pulmonary disease. Seventeen patients with chronic exertional dyspnea were recruited. Patients rated recently recalled breathing discomfort on a numerical rating scale (NRS) and the multidimensional dyspnea profile (MDP). They then performed graded exercise using an arm-ergometer. The NRS was completed following each exercise grade, and the MDP was repeated after a pre-defined dyspnea threshold was reached. During separate visits, patients received either aerosol saline or 80 mg of aerosol furosemide in a randomized, double-blind, crossover design. After treatment, graded exercise to the pre-treatment level was repeated, followed by completion of the NRS and MDP. Treatment effect was defined as the difference between pre- and post-treatment NRS at end exercise, expressed in absolute terms as % Full Scale. “Responders” were defined as those showing treatment effect ≥ 20% of full scale. Final analysis included 15 patients. Neither treatment produced a statistically significant change in NRS and there was no significant difference between treatments (p = 0.45). There were four “responders” and one patient whose dyspnea worsened with furosemide; two patients were responders with saline, of whom one also responded to furosemide. No adverse events were reported. High dose controlled delivery aerosol furosemide was not statistically different from saline placebo at reducing exercise-induced dyspnea. However, a clinically meaningful improvement was noted in some patients.

Dyspnea is an uncomfortable sensation with the potential to cause psychological trauma. Patients presenting with acute respiratory failure, particularly when tidal volume is restricted during mechanical ventilation, may experience the most distressing form of dyspnea known as air hunger. Air hunger activates brain pathways known to be involved in posttraumatic stress disorder (PTSD), anxiety, and depression. These conditions are considered part of the post-intensive care syndrome. These sequelae may be even more prevalent among patients with ARDS. Low tidal volume, a mainstay of modern therapy for ARDS, is difficult to avoid and is likely to cause air hunger despite sedation. Adjunctive neuromuscular blockade does not prevent or relieve air hunger, but it does prevent the patient from communicating discomfort to caregivers. Consequently, paralysis may also contribute to the development of PTSD. Although research has identified post-ARDS PTSD as a cause for concern, and investigators have taken steps to quantify the burden of disease, there is little information to guide mechanical ventilation strategies designed to reduce its occurrence. We suggest such efforts will be more successful if they are directed at the known mechanisms of air hunger. Investigation of the antidyspnea effects of sedative and analgesic drugs commonly used in the ICU and their impact on post-ARDS PTSD symptoms is a logical next step. Although in practice we often accept negative consequences of life-saving therapies as unavoidable, we must understand the negative sequelae of our therapies and work to minimize them under our primary directive to "first, do no harm" to patients.

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. Dyspnea (air hunger) was evoked by constraining tidal volume during graded hypercapnia. We measured $${\text{PET}}_{{{\text{CO}}_{ 2} }}$$ 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. 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. When the expectation of treatment effect is minimized, a significant reduction in dyspnea in response to saline placebo is uncommon but not impossible.

Because dyspnoea is seldom experienced by healthy people, it can be hard for clinicians and researchers to comprehend the patient’s experience. We collected patients’ descriptions of dyspnoea in their own words during a parent study in which 156 hospitalised patients completed a quantitative multidimensional dyspnoea questionnaire. These volunteered comments describe the severity and wide range of experiences associated with dyspnoea and its impacts on a patients’ life. They provide insights not conveyed by structured rating scales. We organised these comments into the most prominent themes, which included sensory experiences, emotional responses, self-blame and precipitating events. Patients often mentioned air hunger (‘Not being able to get air is the worst thing that could ever happen to you.’), anxiety, and fear (‘Scared. I thought the world was going to end, like in a box.’). Their value in patient care is suggested by one subject’s comment: ‘They should have doctors experience these symptoms, especially dyspnoea, so they understand what patients are going through.’ Patients’ own words can help to bridge this gap of understanding.

International audience; Aerosolized furosemide has been shown to relieve dyspnea; nevertheless, all published studies have shown great variability in response. This dyspnea relief is thought to result from the stimulation of slowly adapting pulmonary stretch receptors simulating larger tidal volume. We hypothesized that better control over aerosol administration would produce more consistent dyspnea relief; we used a clinical ventilator to control inspiratory flow and tidal volume. Twelve healthy volunteers inhaled furosemide (40mg) or placebo in a double blind, randomized, crossover study. Breathing Discomfort was induced by hypercapnia during constrained ventilation before and after treatment. Both treatments reduced breathing discomfort by 20% full scale. Effectiveness of aerosol furosemide treatment was weakly correlated with larger tidal volume. Response to inhaled furosemide was inversely correlated to furosemide blood level, suggesting that variation among subjects in the fate of deposited drug may determine effectiveness. We conclude that control of aerosol delivery conditions does not improve consistency of treatment effect; we cannot, however, rule out placebo effect.

Published studies have shown great variability in response when aerosolized furosemide has been tested as a palliative treatment for dyspnea. We hypothesized that a higher furosemide dose with controlled aerosol administration would produce consistent dyspnea relief. We optimized deposition by controlling inspiratory flow (300–500 ml/s) and tidal volume (15% predicted vital capacity) while delivering 3.4 micron aerosol from either saline or 80 mg of furosemide. We induced dyspnea in healthy subjects by varying inspired PCO2 while restricting minute ventilation. Subjects rated “Breathing Discomfort” on a Visual Analog Scale (BDVAS, 100% Full Scale ≡ intolerable). At the PETCO2 producing 60% BDVAS pre-treatment, furosemide produced a clinically meaningful reduction of BDVAS (i.e., > 20%FS) in 5/11 subjects; saline reduced dyspnea in 3/11 subjects; neither treatment worsened dyspnea in any subject. Furosemide and saline treatment effects were not statistically different. There were no significant adverse events. Higher furosemide dose and controlled delivery did not improve consistency of treatment effect compared with prior studies.

Several studies have mapped brain regions associated with acute dyspnea perception. However, the time-course of brain activity during sustained dyspnea is unknown. Our objective was to determine the time-course of neural activity when dyspnea is sustained. Eight healthy subjects underwent brain blood oxygen level dependent functional magnetic imaging (BOLD-fMRI) during mechanical ventilation with constant mild hypercapnia (~45 mmHg). Subjects rated dyspnea (air hunger) via visual analog scale (VAS). Tidal volume (VT) was alternated every 90 seconds between high VT (0.96±0.23 L) that provided respiratory comfort (12±6% full scale) and low VT (0.48±0.08 L) which evoked air hunger (56±11% full scale). BOLD signal was extracted from a priori brain regions and combined with VAS data to determine air hunger related neural time-course. Air hunger onset was associated with BOLD signal increases that followed two distinct temporal profiles within sub-regions of the anterior insula, anterior cingulate and prefrontal cortices (cortico-limbic circuitry): (1) fast, BOLD signal peak 40 seconds. BOLD signal during air hunger offset followed fast and slow temporal profiles symmetrical, but inverse (signal decreases) to the time-courses of air hunger onset. We conclude that differential cortico-limbic circuit elements have unique contributions to dyspnea sensation over time. We suggest that previously unidentified sub-regions are responsible for either the acute awareness or maintenance of dyspnea. These data enhance interpretation of previous studies and inform hypotheses for future dyspnea research.

Rationale: Opioids are commonly used to relieve dyspnea, but clinical data are mixed and practice varies widely. Objectives: Evaluate the effect of morphine on dyspnea and ventilatory drive under well-controlled laboratory conditions. Methods: Six healthy volunteers received morphine (0.07 mg/kg) and placebo intravenously on separate days (randomized, blinded). We measured two responses to a CO2 stimulus: (1) perceptual response (breathing discomfort; described by subjects as “air hunger”) induced by increasing partial pressure of end-tidal carbon dioxide (PetCO2) during restricted ventilation, measured with a visual analog scale (range, “neutral” to “intolerable”); and (2) ventilatory response, measured in separate trials during unrestricted breathing. Measurements and Main Results: We determined the PetCO2 that produced a 60% breathing discomfort rating in each subject before morphine (median, 8.5 mm Hg above resting PetCO2). At the same PetCO2 after morphine administration, median breathing discomfort was reduced by 65% of its pretreatment value; P < 0.001. Ventilation fell 28% at the same PetCO2; P < 0.01. The effect of morphine on breathing discomfort was not significantly correlated with the effect on ventilatory response. Placebo had no effect. Conclusions: (1) A moderate morphine dose produced substantial relief of laboratory dyspnea, with a smaller reduction of ventilation. (2) In contrast to an earlier laboratory model of breathing effort, this laboratory model of air hunger established a highly significant treatment effect consistent in magnitude with clinical studies of opioids. Laboratory studies require fewer subjects and enable physiological measurements that are difficult to make in a clinical setting. Within-subject comparison of the response to carefully controlled laboratory stimuli can be an efficient means to optimize treatments before clinical trials.

Context Dyspnea is an uncomfortable and distressing sensation experienced by hospitalized patients. Objectives There is no large-scale study of the prevalence and intensity of patient-reported dyspnea at the time of admission to the hospital. Methods Between March 2014 and September 2016, we conducted a prospective cohort study among all consecutive hospitalized patients at a single tertiary care center in Boston, MA. During the first 12 hours of admission to medical-surgical and obstetric units, nurses at our institution routinely collect a patient's 1) current level of dyspnea on a 0–10 scale with 10 anchored at "unbearable," 2) worst dyspnea in the past 24 hours before arrival at the hospital on the same 0–10 scale, and 3) activities that were associated with dyspnea before admission. The prevalence of dyspnea was identified, and tests of difference were performed across patient characteristics. Results We analyzed 67,362 patients, 12% of whom were obstetric patients. Fifty percent of patients were admitted to a medical-surgical unit after treatment in the emergency department. Among all noncritically ill inpatients, 16% of patients experienced dyspnea in the 24 hours before the admission. Twenty-three percent of patients admitted through the emergency department reported any dyspnea in the past 24 hours. Eleven percent experienced some current dyspnea when interviewed within 12 hours of admission with 4% of patients experiencing dyspnea that was rated 4 or greater. Dyspnea of 4 or more was present in 43% of patients admitted with respiratory diagnoses and 25% of patients with cardiovascular diagnoses. After multivariable adjustment for severity of illness and patient comorbidities, patients admitted on the weekend or during the overnight nursing shift were more likely to report dyspnea on admission. Conclusion Dyspnea is a common symptom among all hospitalized patients. Routine documentation of dyspnea is feasible in a large tertiary care center.

BACKGROUND:Dyspnea (breathing discomfort) can be as powerfully aversive as pain, yet is not routinely assessed and documented in the clinical environment. Routine identification and documentation of dyspnea is the first step to improved symptom management and it may also identify patients at risk of negative clinical outcomes. OBJECTIVE:To estimate the prevalence of dyspnea and of dyspnea-associated risk among hospitalized patients. DESIGN:Two pilot prospective cohort studies. SETTING:Single academic medical center. PATIENTS:Consecutive patients admitted to four inpatient units: cardiology, hematology/oncology, medicine, and bariatric surgery. MEASUREMENTS:In Study 1, nurses documented current and recent patient-reported dyspnea at the time of the Initial Patient Assessment in 581 inpatients. In Study 2, nurses documented current dyspnea at least once every nursing shift in 367 patients. We describe the prevalence of burdensome dyspnea, and compare it to pain. We also compared dyspnea ratings with a composite of adverse outcomes: 1) receipt of care from the hospital's rapid response system, 2) transfer to the intensive care unit, or 3) death in hospital. We defined burdensome dyspnea as a rating of 4 or more on a 10-point scale. RESULTS:Prevalence of burdensome current dyspnea upon admission (Study 1) was 13% (77 of 581, 95% CI 11%-16%). Prevalence of burdensome dyspnea at some time during the hospitalization (Study 2) was 16% (57 of 367, 95% CI 12%-20%). Dyspnea was associated with higher odds of a negative outcome. CONCLUSIONS:In two pilot studies, we identified a significant symptom burden of dyspnea in hospitalized patients. Patients reporting dyspnea may benefit from a more careful focus on symptom management and may represent a population at greater risk for negative outcomes.

Study objectives: We sought to improve speech in tracheostomized individuals receiving positivepressure ventilation. Such individuals often speak with short phrases, long pauses, and have problems with loudness and voice quality. Subjects: We studied 15 adults with spinal cord injuries or neuromuscular diseases receiving long-term ventilation. Interventions: The ventilator was adjusted using lengthened inspiratory time (TI), positive end-expiratory pressure (PEEP), and combinations thereof. Results: When TI was lengthened (by 8 to 35% of the ventilator cycle), speaking time increased by 19% and pause time decreased by 12%. When PEEP was added (5 to 10 cm H2O), speaking time was 25% longer and obligatory pauses were 21% shorter. When lengthened TI and PEEP were combined (with or without reduced tidal volume), their effects were additive, increasing speaking time by 55% and decreasing pause time by 36%. The combined intervention improved speech timing, loudness, voice quality, and articulation. Individual differences in subject response to the interventions were substantial in some cases. We also tested high PEEP (15 cm H2O) in three subjects and found speech to be essentially identical to that produced with a one-way valve. Conclusions: These simple interventions markedly improve ventilator-supported speech and are safe, at least when used on a short-term basis. High PEEP is a safer alternative than a one-way valve. (CHEST 2003; 124:1512–1521)

Air hunger (uncomfortable urge to breathe) is a component of dyspnea (shortness of breath). Three human H215O positron emission tomography (PET) studies have identified activation of phylogenetically ancient structures in limbic and paralimbic regions during dyspnea. Other studies have shown activation of these structures during other sensations that alert the organism to urgent homeostatic imbalance: pain, thirst, and hunger for food. We employed blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine activation during air hunger. fMRI conferred several advantages over PET: enhanced signal-to-noise, greater spatial resolution, and lack of ionizing radiation, enabling a greater number of trials in each subject. Six healthy men and women were mechanically ventilated at 12–14 breaths/min. The primary experiment was conducted at mean end-tidal Pco2of 41 Torr. Moderate to severe air hunger was evoked during 42-s epochs of lower tidal volume (mean = 0.75 L). Subjects described the sensation as “like breath-hold,” “urge to breathe,” and “starved for air.” In the baseline condition, air hunger was consistently relieved by epochs of higher tidal volume (mean = 1.47 L). A control experiment in the same subjects under a background of mild hypocapnia (mean end-tidal PCO2= 33 Torr) employed similar tidal volumes but did not evoke air hunger, controlling for stimulus variables not related to dyspnea. During each experiment, we maintained constant end-tidal Pco2and PO2to avoid systematic changes in global cerebral blood flow. Whole-brain images were acquired every 5 s (T2*, 56 slices, voxel resolution 3 × 3 × 3 mm). Activations associated with air hunger were determined using voxel-based interaction analysis of covariance that compared data between primary and control experiments (SPM99). We detected activations not seen in the earlier PET study using a similar air hunger stimulus ( Banzett et al. 2000 ). Limbic and paralimbic loci activated in the present study were within anterior insula (seen in all 3 published studies of dyspnea), anterior cingulate, operculum, cerebellum, amygdala, thalamus, and basal ganglia. Elements of frontoparietal attentional networks were also identified. The consistency of anterior insular activation across subjects in this study and across published studies suggests that the insula is essential to dyspnea perception, although present data suggest that the insula acts in concert with a larger neural network.

We directly compared convergent, discriminant and concurrent validity of the Dyspnoea-12 (D-12) and Multidimensional Dyspnoea Profile (MDP) in people with chronic obstructive pulmonary disease.Breathlessness measures (D-12, MDP, visual analogue scales and descriptors) were completed for two focal periods (daily life and end of walk test). Instrument structure (D-12 and MDP item grouping) was assessed with factor analysis. Differences between airflow severity stage and focal periods (ANOVA, t-test and Chi-squared test), associations between D-12 and MDP (r, r

Dyspnoea is defined as “breathing discomfort” [1]. The paper by GrOnseth et al. [2] in this issue of European Respiratory Journal ( ERJ ) reports the prevalence of dyspnoea in 15 countries throughout the world. There are few studies of dyspnoea in the general population available, so this added information is welcome. The overall prevalence of dyspnoea in their study population was 27%, which is not far out of line with several other studies dating from 1964 to the present [3–5]. Some studies, based on review of medical records, have reported much lower prevalence [6]. However, patients may neglect to report dyspnoea to their clinician because they think it does not reach a sufficient level of importance, or clinicians may fail to record what their patients say. Requiring patients to scale their symptoms can result in more uniform reporting, because the patient does not have to decide how much is reportable, it takes very little time and it facilitates uniform documentation. Busy clinicians may ask “is dyspnoea worth documenting?” One powerful argument for routine assessment is the need to reduce suffering, as with pain. A second argument is the emerging predictive value of dyspnoea in forecasting medical needs. In addition to being prevalent, “dyspnoea” is a powerfully aversive sensation [7] and patients deserve adequate management of this symptom, as passionately argued by Currow et al. [8]. Effective interventions exist and should be used [9–11]; assessing dyspnoea is the first step in managing it. Dyspnoea is frequently overlooked despite its prevalence and the severity of distress it causes [12]. For example, despite having had dyspnoea for months a majority of advanced cancer patients had not received any treatment for it [ …

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.

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.

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 (P0.02, Wilcoxon signed rank). Median AIR HUNGER increased 2.5 points with paralysis during hypercapnic (P0.02) 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.

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.

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 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 P et CO 2 ) 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.

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.

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.

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%).

We present a simple and reliable method to calibrate respiratory magnetometers and Respitrace to infer respiratory volume changes. As in earlier methods, we assume two degrees of freedom in the chest wall and that volume displacement depends linearly on surface motion at the rib cage and abdomen. Because the area of the rib cage is larger, a given motion of its surface produces a greater lung volume change; therefore, the rib cage motion signal is given a larger gain before the two signals are added to estimate volume. In contrast to earlier methods, we use a “standard ratio” to weight relative gains of the rib cage and abdominal signals for all subjects rather than determining a gain ratio for each individual subject. Our procedure does not require subjects to perform the sometimes difficult isovolume maneuvers used in the calibration method of Konno and Mead (J. Appl. Physiol. 22: 407–422, 1967), does not require statistical computation used in the multiple-breath linear regression method, and does not produce the occasional substantial errors in gain ratio that may occur with the other methods. When magnetometers are used, the standard ratio is 4:1 (rib cage-to-abdomen); when Respitrace is used, the standard ratio is 2:1. In 11 subjects, calibration with standard ratios was as accurate as the isovolume and linear regression techniques. Accuracy during normal breathing was nearly always within 10% (median 2%), but occasional large errors occurred with both instruments.

Background Most measures of dyspnea assess a single aspect (intensity or distress) of the symptom. We developed the Multidimensional Dyspnea Profile (MDP) to measure qualities and intensities of the sensory dimension and components of the affective dimension. The MDP is not indexed to a particular activity and can be applied at rest, during exertion, or during clinical care. We report on the development and testing of the MDP in patients with a variety of acute and chronic cardiopulmonary conditions. Methods One hundred fifty-one adults admitted to the ED with breathing symptoms completed the MDP three times in the ED, twice at least 1 h apart (T1, T2), and near discharge from the ED (T3). Measures were repeated in 68 patients twice in a follow-up session 4 to 6 weeks later (T4-T5). The ED sample was 56% men with a mean age of 53 ± 15 years; the follow-up sample was similar. Results Factor analysis resulted in a two-factor solution with a total explained variance of 63%, 74%, and 72% at T1, T2, and T3, respectively. One domain related to primary sensory qualities and immediate unpleasantness, and the second encompassed emotional response. For the two domains, Cronbach α ranged from 0.82 to 0.95, and the intraclass correlation coefficient ranged from 0.91 to 0.98. Repeated-measures analysis was significant for change (T1, T3, T4), showing responsiveness to change in MDP domains with treatment (F[2,66] = 19.67, P > .001). Conclusions These analyses support the reliability, validity, and responsiveness to clinical change of the MDP with two domains in an acute care and follow-up setting.

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 incubated using topical anesthesia, then subjects were completely paralyzed with vecuronium and mechanically ventilated at various endtidal partial pressure of carbon dioxide (P ET CO 2 ) levels, all without sedation. Measurements and Main Results: Heart rate (HR), blood pressure, oxygen saturation by pulse oximeter (SpO 2 ), and P ET CO 2 were measured. Sul bjects' 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 mention. Subjects felt breathless when P ET CO 2 was even slightlyelevated. 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' SPO 2 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 PCO 2 , adequate sedation and analgesia, minimization of pain during procedures, psychological support, and maintenance of communication when possible.

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.

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.

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.

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.

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.

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.

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.

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.

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.

We recorded the responses of 21 slowly adapting pulmonary stretch receptors (PSRs) and 8 rapidly adapting pulmonary stretch receptors (RARs) from the vagi of anesthetized open-chest dogs to high-frequency ventilation (HFV) at 15 Hz, at constant mean end-expiratory lung volume, and constant end-tidal PCO2. HFV applied in this way has been shown to prolong expiration. The responses of pulmonary afferents during HFV at constant mean volume have not been described. In the present experiments, receptor discharge during HFV was compared with that during the end-expiratory pause of normal-frequency ventilation. Average PSR discharge increased when HFV was applied, although not all PSRs exhibited increases. RARs were generally silent during normal and high-frequency ventilation at functional residual capacity and above. However, at low lung volumes, RAR discharge increased greatly when HFV was applied. We conclude that PSR discharge is increased during HFV in the absence of increased lung volume and that increases in PSR discharge during HFV are sufficient to explain the reflex that prolongs expiration in dogs.

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.

High frequency (15 Hz), low volume (approximately 40 ml) oscillation of the respiratory system lengthens expiration in anesthetized dogs even in the absence of changes in mean expiratory lung volume or blood gases (Banzett et al ., 1983). Although vagotomy abolishes this response, we felt it might mask the reflex rather than interrupt the afferent pathway. To ascertain whether pulmonary and airway afferents alone are capable of evoking this reflex, we confined the oscillatory stimulus to the lung by widely opening the chest. The dogs were paralyzed but breathed ‘spontaneously’ by means of a solenoid valve opened and closed by the phrenic neurogram. End-expiratory lung volume and P CO2 were held constant. All eight dogs that were tested after thoracotomy lengthened expiration during oscillation. Although quantitative comparisons of responses before and after thoracotomy are not entirely reliable, we could see no consistent change in the strength of response with paralysis or with thoracotomy. We conclude that the principal afferent limb of the ventilatory reflex response to oscillation arises in the lungs and intrathoracic airways.