Respiratory sensations in asthma: physiological and clinical implications.

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

Midlatency respiratory-related somatosensory activity and perception of oral pressure pulses in normal humans.

A direct relationship exists within subjects between midlatency features (<100 ms poststimulus) of respiratory-related evoked potentials and the perceived magnitude of applied oral pressure pulse stimuli. We evaluated perception in 18 normal subjects using cross-modality matching of applied pressure pulses via grip force and estimated mechanoafferent activity in these subjects by computing the global field power (GFP) from respiratory-related evoked potentials recorded over the right side of the scalp. We compared across subjects 1) the predicted magnitude production for a standard pressure pulse and 2) the slope (beta) and 3) the intercept (INT) of the Stevens power law to the summed GFP over 20-100 ms poststimulus. Both the magnitude production for a standard pressure pulse and the beta showed an inverse relationship with the summed GFP over 20-100 ms poststimulus, although there was no relationship between INT and the summed GFP. This may partially reflect characteristics of the mechanosensors and surely includes aspects of cognitive judgment, because we found and corrected for a high correlation between, respectively, beta (and INT) for pressure pulses and beta (and INT) for estimation of line lengths, a nonrespiratory modality. The relatively shallow, even inverse GFP-to-perception relationship suggests that, despite marked differences in the magnitude of afferent traffic, normal subjects seem to perceive things similarly.

Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading.

Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.

Pathophysiology of dyspnea.

Dyspnea may be defined as an uncomfortable sensation of breathing. The sense of respiratory effort, chemoreceptor stimulation, mechanical stimuli arising in lung and chest wall receptors, and neuroventilatory dissociation may all contribute to the sensation of dyspnea. Different mechanisms likely give rise to qualitatively different sensations of dyspnea. In most patients, dyspnea is probably due to a combination of mechanisms. For example, in asthma, a heightened sense of effort, neuroventilatory dissociation, and vagal stimuli arising from bronchoconstriction and airway inflammation may all play a role. Patients with different disorders and different mechanisms of dyspnea use different phrases to describe their breathing discomfort. Hence, the language patients use to describe their dyspnea may provide clues to the etiology of their symptoms.

Respiratory control and respiratory sensation in a patient with a ganglioglioma within the dorsocaudal brain stem.

We encountered a young woman with severe central sleep apnea caused by a medullary glioma located slightly dorsal to and to the right of the midline, a region not generally associated with CO(2) chemosensitivity. The patient had normal spirometric readings, lung volumes, diffusing capacity, maximal inspiratory pressure, and alveolar-arterial oxygen difference. While awake, she displayed marked irregularity in her breathing pattern; her end-tidal CO(2) (FET(CO(2))) ranged from 5.3 to 10.9%. During voluntary hyperpnea, she could quickly reduce her FET(CO(2)) to 4.2%, but her PCO(2) did not change after administration of acetazolamide or progesterone. Like patients with congenital central hypoventilation syndrome (CCHS), our patient had a relatively intact ventilatory response to exercise; her PCO(2) was high at the start of exercise and increased slightly thereafter. In contrast to CCHS patients, however, our patient had an intact hypoxic ventilatory response (DeltaVE/ DeltaSa(O(2)) = -0.37 L/min/Sa(O(2))). In further contrast to CCHS patients, our patient had a very short breathholding time and described a sensation of air hunger as the factor limiting her breathholding ability. Her heart rate and blood pressure responses to the Valsalva maneuver were normal.

Bronchodilator therapy in chronic obstructive pulmonary disease.

This paper reviews new developments in bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Most patients with COPD respond to bronchodilators, but we have no reliable way to predict which patients will respond. When responsiveness is assessed, changes in lung volume as well as improvements in FEV1 should be considered. The combination of a beta-agonist and an anticholinergic agent produces greater improvement than either agent alone. Anticholinergic agents have few adverse side effects in patients with COPD, but concern remains about the possible cardiac side effects of beta-agonists. No clear answer exists about whether new, long-acting beta-agonists, such as salmeterol, should supplant anticholinergic agents as "first-line" therapy in COPD.

Contribution of supraglottal mechanoreceptor afferents to respiratory-related evoked potentials in humans.

We used the global field power (GFP) to estimate the magnitude and timing of activation of the somatosensory cortex by respiratory mechanoreceptor afferents in normal humans in response to brief, negative oral pressure pulses applied at the onset of inspiration. We compared responses before (test) and after insertion of a laryngeal mask airway (LMA) that prevented supraglottal airway receptors from sensing the applied stimulus. Evoked potential responses without supraglottic stimulation were smaller, with delayed or missing features, than those with all receptors stimulated. Supraglottic receptors contribute about one-half of the GFP summed over the 100 ms poststimulus, and subglottal receptors, including those in the larynx, provide a GFP response approximately 38% above baseline. The most obvious difference between test and LMA responses occurred at 55 ms on average, when the LMA GFP lacked activation features seen in the test condition. We conclude that mechanoreceptors above the larynx are responsible for a major portion of the midlatency afferent information arriving at the somatosensory cortex in response to applied pressure pulses.

Effect of inspiratory flow rate on respiratory sensation and pattern of breathing.

We examined the effect of inspiratory flow rate (IFR) on respiratory sensation during mechanical ventilation in 10 normal subjects. We adjusted the ventilator tidal volume (VT), frequency, and IFR until subjects indicated that they were maximally comfortable ("comfort IFR"). Subjects then rated breathing discomfort on a visual analog scale (VAS) while IFR was varied among four levels: 70%, 100%, 200%, and 300% of the comfort IFR. When compared with VAS ratings at the comfort IFR (4.4 +/- 1.2, mean +/- SEM), VAS ratings were significantly greater at the lowest (i.e., 70% comfort; 12.1 +/- 2.1) and highest (300% comfort; 8.2 +/- 0.9) IFR; there was no difference in ratings between the comfort IFR and 200% comfort IFR. At the lowest IFR, the breathing discomfort arose in the chest and had an air hunger-like quality; at high IFR, the discomfort arose in the upper airway. In the second portion of the study, subjects used open magnitude estimation to rate breaths of five different sizes at three different IFR (70%, 100%, and 200% of comfort rate). Neither the exponent nor intercept for VT perception differed among the three IFR. Our results demonstrate that although IFR does not alter magnitude estimation of breath size, deviations of IFR from that desired by the subject may greatly affect respiratory comfort.

Tidal volume perception in normal subjects: the effect of altered arterial PCO2.

We examined the relationship between tidal volume (VT) perception and level of CO2. Ten normal subjects were connected to a volume-cycled ventilator set in control mode, and VT and respiratory rate were adjusted until subjects were comfortable. At 2 levels of CO2 which differed by 6-8 mmHg, subjects rated ten different ventilator tidal volumes which ranged from 40-200% of the VT that made them comfortable at the lower CO2. Despite large differences in inspiratory muscle activity, there was no significant difference between the two levels of CO2 for either the exponent [1.39 +/- 0.35 vs 1.36 +/- 0.49 (low CO2 vs high CO2, mean +/- SD), P > 0.5] or constant (-0.09 +/- 0.12 vs -0.14 +/- 0.17, P > 0.1) for VT perception. For the group, there was no correlation between the hypercapnic ventilatory response (HCVR) measured by rebreathing and the exponent for VT perception. We conclude that: (1) the level of CO2 does not influence magnitude estimation of VT; (2) respiratory muscle activity is not essential to VT perception; and (3) there is no correlation between the HCVR and magnitude estimation of VT.

Peak airway pressure: why the fuss?

The preponderance of evidence indicates that high airway pressure is not by itself injurious to the lung. Rather, overdistention of the lung appears to be the fundamental mechanism underlying VALI. The physician must bear in mind the factors (ie, flow-resistive pressure losses, respiratory muscle activity, and abnormalities in rib cage or abdominal compliance) that may alter the relationship between PAP and lung volume. Under some circumstances, high PAP may, in fact, reflect lung overdistention, and maneuvers that minimize overdistention may also reduce PAP. Similarly, the goal of improving oxygenation may sometimes entail strategies (such as prolonging inspiratory time) that lower PAP. In these settings, however, the reduction in PAP should be regarded as a by-product of achieving another therapeutic goal and not an end point in and of itself. In other settings, such as the mechanically ventilated patient with severe airflow obstruction, measures that lower PAP by reducing inspiratory flow rate may worsen pulmonary hyperinflation, and thereby increase the risk of complications.

Molecular confirmation of bacillus Calmette-Guérin as the cause of pulmonary infection following urinary tract instillation.

Instillation into the urinary tract of the bacillus Calmette-Guérin (BCG), a strain of Mycobacterium bovis, is associated only rarely with severe side effects. We report here two cases of culture-proven pulmonary infection due to therapy with BCG. The first patient, who was seropositive for the human immunodeficiency virus, developed bilateral interstitial pneumonitis after instillation of BCG into the bladder. The second patient developed a right-lower-lobe infiltrate and empyema after instillation of BCG into the right renal pelvis. The clinical isolates from these two patients and from a third patient with a psoas abscess following intravesical instillation were analyzed with use of pulsed field gel electrophoresis (PFGE) to resolve chromosomal restriction fragment polymorphisms. The clinical isolates were confirmed to be BCG by comparison with known vaccine strains that differed from M. bovis isolates. We conclude that the potential for subsequent dissemination be considered prior to the intravesical administration of BCG. Analysis with PFGE may be useful for identifying species of the Mycobacterium tuberculosis complex.

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

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

Ventilatory and P0.1 response to hypercapnia in quadriplegia.

Unlike individuals with comparable degrees of respiratory muscle weakness from other causes, quadriplegic patients have a blunted ventilatory and P0.1 response to hypercapnia. This suggests that the diminished response in quadriplegia is due, in part, to an alteration in respiratory drive. We measured the hypercapnic response in 9 subjects with chronic quadriplegia (Q) and 8 normal controls (N). Ventilatory muscle strength, maximum voluntary ventilation (MVV), and lung volumes were measured in all subjects. The ventilatory response (HCVR) in Q was significantly less than in N (0.73 +/- 0.37 vs 2.95 +/- 0.4 L.min-1.mmHg-1; P less than 0.001), even when normalized for indices of respiratory muscle performance (e.g., vital capacity, MVV). There was no significant change in the HCVR in Q after the administration of naloxone. We also serially studied 2 subjects with acute quadriplegia, and found that despite progressive improvement in respiratory muscle performance, there was no accompanying increase in the response to hypercapnia. These data suggest that muscle weakness alone cannot explain the blunted hypercapnic response in quadriplegia, and are consistent with the hypothesis that these subjects have a reduced ventilatory drive.

Considerations regarding the application of capillary optics to medical radiography.

The generation of monoenergetic or quasimonoenergetic x-ray spectra has been accomplished by several methods including the use of K-edge filtration, characteristic radiation, crystal monochromators, and multilayer mirrors. In this paper some practical questions are discussed regarding the possibility of obtaining narrow-band spectra using x-ray reflection in glass capillary optics which have been reported recently in connection with the focusing and generation of parallel x-ray beams. Derivation of formulas for double and triple reflection with and without additional K-edge filtration imply that these methods are superior to the use of filtration alone. It is shown that the double reflection scheme is most sensitive to the angular divergence of the beam emanating from the capillary array used to generate the incident parallel beam. Simulations using three reflections predict output spectra which are relatively insensitive to blurring due to angular divergence. A small amount of K-edge filtration in combination with three reflections provides considerable sharpening of the x-ray spectrum. Aside from the spectral selectivity provided by the capillary array, the reduced divergence of the primary transmission may have advantages for scatter rejection in situations where the air gap between the patient and detector is increased by an amount consistent with the resolution requirements of the application. In parallel beam situations, the use of capillary arrays between the patient and detector may also be useful for the rejection of divergent scattered radiation.

A K alpha dual energy x-ray source for coronary angiography.

The use of characteristic-line radiation from rare-earth targets bombarded by high-energy (up to 1 MeV) electron beams has been evaluated as an x-ray source for dual energy K-edge subtraction imaging of the human coronary arteries. Two characteristic-line x-ray sources, one using the split K alpha 1 and K alpha 2 lines of lanthanum excited by a high-energy electron beam and the other using the K alpha lines of barium and cerium, were studied. A Monte Carlo electron-photon simulation was used to calculate x-ray spectra and energy deposition profiles from targets of these elements bombarded by electrons in the energy range 140 keV to 1 MeV. A general dual-energy imaging model was developed that used these calculated source spectra to numerically investigate the dependence of the subtraction image signal-to-noise ratio on such factors as the ratio of K-line to x-ray continuum yield, continuum spectral shape, x-ray filtering, and detector response. A signal averaging technique for enhancing the signal-to-noise ratio was also evaluated. The results of these calculations were used to identify an optimum electron beam, target, filter, and detector configuration. A compact electron accelerator capable of providing the required electron beam parameters was designed. Calculations indicate that under ideal conditions the optimized system would be capable of imaging 2 mg/cm2 of iodine contrast agent in 20 g/cm2 of tissue with a signal-to-noise ratio of 5, a detector pixel size of 0.25 mm2, and a total image acquisition time of 10 ms. These parameters are consistent with those needed to image the human coronary arteries after an intravenous injection of iodine contrast agent. These capabilities, along with the relatively modest hardware requirements of this system, make it attractive as an x-ray source for dual energy transvenous coronary angiography.