Abstract
The perception of inspiratory resistive (R) loads was studied in nonasthmatic children and in children with a history of life-threatening asthma. It was hypothesized that the children with life-threatening asthma would have a reduced sensitivity to added mechanical loads as measured by magnitude estimation of resistive loads (ME). The subjects were screened from the experimenter and seated in a sound-isolated room in a lounge chair facing an oscilloscope, and they respired through a nonbreathing valve with the inspiratory port connected to the loading manifold. The oscilloscope displayed the inspiratory V˙, and each subject was required to inspire to the same peak V˙ for each breath. The subject's inspiratory background R was measured by the interrupter method. Five magnitudes of R loads and no-load were presented randomly 10 times each for a single inspiration after the illumination of a light cue. The subjects were initially given a training trial breathing to the V˙ target. The loads were presented in two trials. The load was estimated using the modified Borg scale. The slope of the log-log relationship between R load magnitude and the ME is a measure of the sensitivity of the subject to R loads. The slope for children with life-threatening asthma was significantly less than that for asthmatic and nonasthmatic children. There were no significant differences in the slope related to race, sex or age in the nonasthmatic children or in the asthmatic children. The reduced sensitivity to increased R loads suggests that these children are at risk of a life-threatening asthmatic attack in part because of an underestimation or delay in the perception of the increased mechanical load that occurs during an asthmatic attack.
Asthma is a chronic lung disease characterized by recurrent reversible airway obstruction, airway inflammation, and airway hyperresponsiveness. Morbidity and mortality from asthma have increased during the last decade despite better treatment and increase in the understanding of the pathophysiology of asthma (1-5). Significant increase in mortality is seen in asthmatics between 10 and 14 yr of age and in those older than 50 yr of age (4).
A large number of previous studies have investigated the growing problem associated with asthma death (4, 6-8). Most of these studies were epidemiologic and did not address the pathophysiologic processes and the mechanisms causing death. These studies accordingly listed the profile of asthmatics who were fatality prone (1, 5, 9, 10). One of the factors leading to asthma death may be underestimation of the severity of an asthmatic attack because of reduced perception. Poor perception was first described by Rubinfeld and Pain (11). Recently, Kikuchi and colleagues (12) studied adults with near-fatal asthma and found a marked reduction in the perceptual sensitivity to resistive loads compared with that in normal control subjects. In this study, subjects were allowed to breathe freely for both control and loaded breaths, i.e., they did not target airflow or volume. It is common for some subjects, including asthmatic patients, to decrease inspiratory flow during a resistive loaded breath. Resistive loads are airflow-dependent loads and a decrease in the inspiratory airflow reduces the pressure and airflow changes associated with the increased load. The decrease in these load-related mechanical parameters with a decreased inspiratory effort can result in a reduced sensory stimulation and underestimation of the load magnitude. If the asthmatic patients reduce airflow for a loaded breath more than nonasthmatic subject do, then the measured sensitivity (ME) slope to the added loads will be underestimated.
The present study used airflow targeting for both loaded and unloaded breaths to determine the perceptual sensitivity of an added external mechanical load to the airways of children with life-threatening asthma, those with stable asthma, and those without asthma using the modified Borg scale (13). It was hypothesized that children with a history of life-threatening asthma would have a decreased sensitivity to external resistive loads when the inspiratory airflow was maintained.
Three groups of children were tested in this study: (1) subjects (n = 10) with life-threatening asthma (LTA), (2) subjects (n = 9) with stable asthma (A), and (3) nonasthmatic (NA) subjects (n = 10). The subject ages in all the groups ranged between 8 and 23 yr. The subjects in the asthma control group, A (children without a history of life-threatening asthma) were similar in age, sex, race, and severity of asthma compared with those in the LTA group. The nonasthmatic subject group was also similar in the distribution of age, sex, and race. All patients with asthma were followed at the Pediatric Pulmonary Clinic at Shands Hospital, University of Florida, Gainesville, Florida. The diagnosis of asthma was made by a pediatric pulmonologist based on American Thoracic Society criteria (14). The University of Florida Health Science Center Institutional Review Board approved the study.
The 10 LTA subjects were asymptomatic without exacerbation of their asthma within 4 wk of the study. All these subjects had been admitted to the pediatric intensive care unit with acute respiratory failure, that is, with severe hypoxia and retention of carbon dioxide. Two of the subjects presented with loss of consciousness and hypoxic seizure. Five of the 10 required mechanical ventilation for 1 to 3 d. The other three subjects were managed with oxygen and continuous ventolin by nebulizer. The subjects with LTA were maintained on inhaled corticosteroids and theophylline. The subjects in the control A group had moderate asthma and were also receiving daily maintenance treatment to control their symptoms. However, the control A subjects had never been admitted to the intensive care unit because of respiratory failure. The NA subjects were recruited from the local schools and were free of chronic respiratory disease. These subjects were also free of any acute respiratory disease at least 4 wk prior to the study. In all three groups, none of the subjects had previously participated in studies of respiratory load perception.
The subject was seated comfortably in a lounge chair in a sound-isolated chamber, separated from the experimenter and the experimental apparatus. The subject respired through a mouthpiece (Figure 1) and nonrebreathing valve (2600 series; Hans Rudolph, Kansas City, MO). Care was taken to suspend the valve to eliminate the need for the subject to bite the mouthpiece yet maintain an airtight seal. The resistive loads were sintered bronze disks place in series in a Plexiglas® tube (loading manifold) with stoppered ports between the disks (Figure 1). The loading manifold was connected to a pneumotachograph, which was connected by reinforced tubing on the inspiratory port of the nonbreathing valve. The loading manifold was hidden from the subject's view. Mouth pressure (Pm) was recorded from a port in the center of the nonrebreathing valve. Pm was sensed with a differential pressure transducer and a signal conditioner. Inspiratory airflow (V˙i) was recorded with a differential pressure transducer and signal conditioner connected to the pneumotachograph. The V˙i was integrated to obtain the inspired volume (Vi). The Pm, V˙i, and Vi were recorded on a polygraph. The V˙i was also displayed on an oscilloscope placed in front of the subject. Resistances were selected by removing the stopper and allowing the subject to breathe through the selected port. The V˙i signal from the pneumotachograph displayed on an oscilloscope screen was used by the subjects to target their breathing. They were monitored with a video camera throughout the study.
Pulmonary function tests (FVC, FEV1, and FEV1/FVC) recorded with forced expiratory maneuvers were performed. Airway resistance (Raw) was measured with the interrupter method (15) at the end of the second trial. Briefly, an occlusion valve with a closure time of 2 ms was placed on the minimum resistance port of the loading manifold. At least 10 inspirations were interrupted near peak V˙. Each interrupted inspiration was separated by two to three uninterrupted breaths. The resistance was determined as described by Jackson and colleagues (15).
Informed consent was obtained from each subject and his or her parent or guardian upon arrival to the laboratory. Simple instructions were given, and the subject was allowed to practice V˙ targeting. A series of test loads, including the lowest and highest load, were then presented in practice sessions to familiarize the subject with the range of loads.
The presentation of the resistive loads for magnitude estimation was divided into two experimental trials. The first trial consisted of five resistive load magnitudes (2.8, 6.8, 11.6, 21.2, and 41.2 cm H2O/ L/s) and no-load control presented five times each in random order. Each test breath during which one of the load magnitudes (or no-load) was presented was separated by three to six control breaths. During the experimental trial, the subject was given a cue (red light) on the breath immediately preceding the test breath to signal that the next breath was a test breath, which the subject must estimate. The subject inspired to the target V˙ on each breath (control and test). The subject made the estimate immediately after the test breath using the Borg Category scale (13). The appropriate feeling descriptor was estimated and the potentiometer knob was turned to the corresponding number. The investigator was able to read the estimate without disturbing the subject. When all the loads for Trial 1 had been presented, the subject was allowed a minimum of 5 min rest period. Trial 2 was then presented exactly as for Trial 1, resulting in a total of 10 presentations of each load magnitude and no-load.
At the end of the second experimental trials, the magnitude estimation results were averaged and plotted against resistive load magnitude on a log-log scale. Any subject providing an estimate for more than three of 10 no-load presentations was excluded from the subject group. If a load was given a 0 scale rating more than five times, then that load was considered to be undetected and not included in the regression analysis. The slope was determined by linear regression analysis. The group average for the slope was determined. Comparison between groups was initially performed using an ANOVA, and post-hoc between-group analysis was performed with Student-Newman-Keuls and Bonferroni's method for paired multiple comparison. The significance criterion was set at p < 0.05.
The mean age, height, and body weight were comparable in the subjects with LTA (Table 1), A (Table 2), and NA (Table 3). There were no significant differences in these parameters between LTA, A, and NA. The mean airway resistance was not significantly different for the three groups.
| Patient No. | Age (yr) | Race/Sex | Height (cm) | Weight (kg) | Raw (cm H2O/L/s) | FVC (L) | FEV1(L) | FEV1/FVC | Years Classed as LTA | Medication | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 13 | W/F | 161 | 54 | 4.06 | 3.37 (95) | 2.83 (90) | 0.84 | 5 | Theophylline, ventolin | ||||||||||
| 2 | 9 | W/M | 136 | 29.5 | 5.99 | 5.34 (109) | 2.83 (67) | 0.53 | 4 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 3 | 13 | W/M | 155 | 42.6 | 3.28 | 4.66 (88) | 3.21 (71) | 0.69 | 3 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 4 | 17 | W/M | 175 | 61.3 | 2.12 | 3.42 (105) | 2.07 (73) | 0.61 | 7 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 5 | 15 | W/M | 178 | 68.1 | 1.48 | 4.08 (94) | 3.21 (86) | 0.79 | 1 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 6 | 16 | W/M | 183.5 | 61.8 | 2.07 | 4.1 (92) | 2.34 (62) | 0.57 | 5 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 7 | 16 | B/M | 173 | 52.5 | 5.42 | 5.09 (96) | 3.83 (84) | 0.75 | 7 | Corticosteroid, theophylline, ventolin | ||||||||||
| 8 | 14 | W/M | 161.3 | 49.3 | 2.74 | 4.45 (96) | 3.39 (85) | 0.76 | 4 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 9 | 20 | H/M | 175 | 98.6 | 3.84 | 2.47 (119) | 1.9 (102) | 0.77 | 4 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| 10 | 12 | B/M | 165 | 54.5 | 4.03 | 3.71 (97) | 2.2 (67) | 0.59 | 3 | Inhaled corticosteroid, theophylline, ventolin | ||||||||||
| Mean | 14.5 | 166.28 | 57.2 | 3.50 | 4.07 | 2.78 | 0.69 | |||||||||||||
| SD | 3.0 | 13.9 | 18.1 | 1.46 | 0.87 | 0.64 | 0.11 |
| Patient No. | Age (yr) | Race/Sex | Height (cm) | Weight (kg) | Raw (cm H2O/L/s) | FVC | FEV1 | FEV1/FVC | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 13 | W/F | 165 | 70.9 | 4.22 | 4.44 (124) | 3.32 (105) | 0.75 | ||||||||
| 2 | 9 | W/M | 137.2 | 37.7 | 6.18 | ND† | ND | ND | ||||||||
| 3 | 13 | W/M | 170 | 64 | 4.1 | 4.38 (107) | 3.09 (88) | 0.71 | ||||||||
| 4 | 18 | W/M | 168 | 94 | 4.16 | 5.97 (135) | 3.58 (94) | 0.6 | ||||||||
| 5 | 15 | W/M | 179.1 | 67.9 | 3.04 | 5.73 (123) | 4.13 (95) | 0.72 | ||||||||
| 6 | 15 | W/M | 175.3 | 90.9 | 3.06 | 4.26 (91) | 3.19 (80) | 0.75 | ||||||||
| 7 | 16 | B/M | 175.3 | 60.7 | 3.22 | 4.34 (99) | 3.66 (97) | 0.84 | ||||||||
| 8 | 14 | W/M | 172.7 | 60 | 3.31 | 6.21 (142) | 4.58 (122) | 0.74 | ||||||||
| 9 | 20 | H/M | 186.7 | 85.5 | 3.21 | ND | ND | ND | ||||||||
| 10 | 14 | B/M | 180 | 99.1 | 2.52 | 4.52 (96) | 3.60 (90) | 0.8 | ||||||||
| Mean | 14.7 | 170.9 | 73.1 | 3.70 | 4.98 | 3.64 | 0.74 | |||||||||
| SD | 3.0 | 13.4 | 19.1 | 1.04 | 0.83 | 0.50 | 0.07 |
| Patient No. | Age (yr) | Race/Sex | Height (cm) | Weight (kg) | Raw (cm H2O/L/s) | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 12 | W/F | 154 | 40.5 | 1.92 | |||||
| 2 | 9 | W/M | 149 | 40.4 | 4.37 | |||||
| 3 | 12 | W/M | 157 | 45 | 3.76 | |||||
| 4 | 18 | W/M | 187 | 93.1 | 3.13 | |||||
| 5 | 15 | W/M | 184 | 65.6 | 2.34 | |||||
| 6 | 15 | W/M | 180 | 66.8 | 1.93 | |||||
| 7 | 15 | B/M | 171 | 48.9 | 3.41 | |||||
| 8 | 14 | W/M | 184 | 65.7 | 2.33 | |||||
| 9 | 23 | H/M | 168.9 | 59.6 | 4.54 | |||||
| 10 | 15 | B/M | 191.7 | 72.7 | 1.92 | |||||
| Mean | 14.8 | 172.7 | 59.8 | 2.97 | ||||||
| SD | 3.8 | 15.1 | 16.6 | 1.02 |
The peak inspiratory V˙ was maintained for all magnitudes of resistive load and was not significantly different between groups (Figure 2). The subjects maintained peak inspiratory V˙ despite the increasing resistance, indicating that the subjects successfully targeted their breathing (Figure 3) during the study.
Fig. 2. Relationship between peak inspiratory airflow and ΔR for the targeted breaths. The group mean ± SD airflow is plotted on the y-axis. The no-load is plotted as 0 added resistance on the x-axis. The open circles and dashed line are for the LTA subjects. The open squares and dotted line are for the A subjects. The open triangles and dash and dotted line are for the NA subjects. There was no significant difference between groups.
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Fig. 3. Polygraph tracing for an LTA subject inspiring against a 21.2 cm H2O/L/s resistive load. The pneumotachograph was connected to the inspiratory line, hence, only inspiratory airflow and volume are recorded. The loaded inspiration is indicated. The subject targeted the airflow to the control peak airflow, which resulted in a more negative Pm.
[More] [Minimize]The maximum pressure (Pmax) increased with increasing resistive load magnitude, and the relationship between Pmax and ΔR was not significantly different between the three groups of subjects (Figure 4). There was an increase in the inspiratory volume change as resistive load magnitude increased (Figure 5). This increase in the volume of air inspired was necessary for the subjects to reach their airflow with the increase in mechanical load magnitude.
Fig. 4. Relationship between peak inspiratory Pm and ΔR for the targeted breaths. The group mean ± SD Pm is plotted on the y-axis. The no-load is plotted as 0 added resistance on the x-axis. The symbols and lines are the same as described in Figure 2. There was no significant difference between groups.
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Fig. 5. Relationship between the inspiratory volume and ΔR for the targeted breaths. The group mean ± SD Pm is plotted on the y-axis. The no-load is plotted as 0 added resistance on the x-axis. The symbols and lines are the same as described in Figure 2. There was no significant difference between groups.
[More] [Minimize]The relationship between the mean Borg score and resistive load magnitude is summarized in Figure 6 for the NA, A, and LTA subjects. The mean Borg score was significantly lower for the subjects with life-threatening asthma than for the nonasthmatic control subjects. The score was again lower when compared with the group with stable asthma even though it was not statistically significant. The decreased slope for the ME versus ΔR for the LTA group occurred despite no significant differences between groups in peak V˙ or peak Pm for each load magnitude.
Fig. 6. The mean magnitude estimation-ΔR slope for each subject group. The slope was determined from the log-log plot of the magnitude estimation-ΔR relationship for each subject. The group mean slope ± SE are plotted on the y-axis. Asterisk indicates that the LTA group slope was significantly (p < 0.05) less than both the NA and the A subject groups. There was no significant difference in slope between the A and the NA groups. A vertical point plot of the individual slopes for each subject group is presented in the inset.
[More] [Minimize]This study has shown that subjects with LTA had a significant decrease in the slope of the magnitude estimation-resistive load relationship, indicating a decreased perceptual sensitivity to added extrinsic resistive loads. This difference cannot be explained by the severity of their asthma because the airway resistances of all study groups were within the normal range and at their baseline at the time of the study. In addition, the decrease in magnitude estimation was not due to a decreased inspiratory flow rate because they inspired to a peak flow target for all breaths. Thus, there appears to be an intrinsic reduced sensitivity to increased resistive loads in children with LTA that places these children at a unique risk of a life-threatening event because of a reduced ability to appropriately estimate the severity of their asthmatic attack.
The patients with LTA, when compared with the control asthmatics, were not significantly different in ventilatory status and asthma stability. At the time of the study, the mean airway resistance for the LTA children was not significantly different from that of the control asthmatic subjects or the nonasthmatic children. All the asthmatic subjects were free of any exacerbation of their asthma for at least a month prior to the study. The three subject groups were able to perform the flow targeting with and without the presence of an inspiratory load. This means that the children were not decreasing inspiratory airflow to minimize the inspiratory effort as the magnitude of the inspiratory load increased. Thus, the decreased sensitivity to inspiratory resistive loads of the LTA children cannot be due to a load-magnitude-related decreased inspiratory effort, difference in airway mechanics, or inability to perform the task. This suggests a perceptual processing deficit unique to these patients with LTA that results in a decreased sensitivity to inspiratory resistive loads.
Earlier investigations of respiratory sensation focused on the psychophysics of respiratory perception (16). These studies were primarily concerned with determining the minimum level of added mechanical load to breathing, usually resistive or elastic, that subjects could detect 50% of the time. This difference threshold was shown to be a constant fraction of the background load intrinsic to the respiratory apparatus and the subject (17). Although more variable, this ratio is the same for normal and patient populations, including asthmatic patients. Respiratory sensations have also been studied using scaling methods that involve estimation of the load magnitude and magnitude production of volume, pressure, ventilation, and frequency (16, 18-20). The results have shown that the perceived magnitude of a load is linearly related to the added load when a log-log transformation is used. Thus, respiratory mechanical load sensation follows the general psychophysical relationship (Steven's Psychophysical Law): R = cSn, where R is the perceived intensity, S is the physical stimulus, c is a constant, and n is the exponent measured as the slope of the log-log relationship between R and S (20), i.e., the magnitude of the sensation and the stimulus intensity is a power function related to the stimulus conditions and type of stimulus. The slope of this relationship is a measure of the perceptual sensitivity for resistive loads. It has been previously demonstrated that human subjects can easily scale mechanical loads, volume, pressure, ventilation, and frequency (16, 18, 19). These psychophysical studies have shown that human subjects can detect the presence and type of load and assign a perceptual scale to respiratory stimuli associated with the mechanics of ventilation.
The behavioral response of an asthmatic patient to an asthmatic attack begins with awareness of an increased difficulty in breathing. The perception of an asthmatic attack then leads to self-management of the symptoms. The ability of asthmatic patients to detect and self-assess the magnitude of an intrinsic asthmatic episode has been well documented (21, 22). In addition, extrinsic respiratory loads have been used to mimic the sensations associated with an asthmatic attack (22-25). The detection and assessment of the magnitude of extrinsic loads in asthmatic and nonasthmatic patients has shown that the sensations elicited by an extrinsic load are similar, but not fully equivalent, to the sensations associated with an intrinsic load such as bronchoconstriction (20). The use of extrinsic loads, however, has allowed for the systematic and controlled investigation of respiratory sensations in patient and normal populations. There is a wide range of perceptual sensitivity to an asthmatic episode with a subpopulation of patients who have a reduced ability to detect their asthma symptoms. The variability of measures of perceptual sensitivity in asthmatic patients suggests that this is a nonhomogenous population. Separating the patients with life-threatening asthmatic attacks from the asthmatic population has resulted in the report of differences in the perceptual response to inspiratory loads of this subgroup when compared with control asthmatic patients and nonasthmatics (12). These adult asthmatic patients, with a history of life-threatening asthmatic attacks, had a decreased slope of their magnitude estimation response to inspiratory resistive loads, demonstrating a decreased ability to grade the differences in magnitude of these loads (12), in agreement with the present results in children with life-threatening asthma. Blunted perception or poor perception of added resistance in asthmatics is considered to be one of the risk factors associated with asthma mortality (12). Poor perception may put the patient at risk by leading to delay in seeking medical attention.
Load-related changes in ventilatory pattern, however, is one of the confounding variables in investigation of the magnitude estimation of inspiratory loads. As the magnitude of an inspiratory resistive load increases, an increased inspiratory effort is required to maintain the inspiratory flow rate and volume. It is well known that subjects breathe to their minimum work of breathing and it is common for inspiratory airflow to decrease as the magnitude of the resistive load increases. This effectively decreases the mechanical load stimulus and can alter the perception of the load (18). It has been our experience that the most common ventilatory response of asthmatic patients to an increased inspiratory resistance is premature cessation of the inspiratory effort as soon as the presence of the load is sensed. A previous report of differences in the magnitude estimation of inspiratory resistive loads between populations of asthmatic subjects (12) did not use airflow targeting, and it is likely that the inspiratory breathing pattern was not the same for each load as the load magnitude increased. In the present study, the subjects were trained to target their inspiratory flow rate. The peak airflow during control breathing was set as their target, which they were able to maintain with each breath (Figure 3). All three groups of subjects were able to target their airflow even in the presence of an inspiratory resistive load as shown by no significant difference between groups in the relationships between peak Pm (Figure 4), peak inspiratory airflow (Figure 2), and load magnitude. The difference between groups in the relationship between magnitude estimation and resistive load magnitude is not due to a difference in ventilatory response to the inspiratory load in the present study and is most probably due to a reduced perceptual sensitivity in the children with life-threatening asthma.
The cause of a reduced perceptual sensitivity to inspiratory resistive loads is unknown. Chronic increases in airway resistance were not present in both the LTA and the control asthmatic children and does not appear to explain the differences in slope of the magnitude estimation relationship. In addition, both groups of asthmatic children were under similar maintenance treatment. All three groups were equally able to perform the tasks. The major difference was inability of the LTA patients to grade differences in load magnitude and an apparent increase in threshold. Future studies on the detection threshold will be necessary to specifically address the change in threshold. It appears that there is an inherent deficit in perceptual sensitivity in these patients with LTA that may be present in a small segment of the general population, but is only life-threatening if their is an asthmatic attack where load perceptual sensitivity is important for recognition of their symptoms. Identification of those patients with a perceptual deficit may lead to improved self-management strategies that will reduce their risk of a life-threatening attack.
The writers acknowledge the technical assistance of Ms. Deborah Dalziel.
| 1. | Benatar S. R.Fatal asthma. N. Engl. J. Med.3141986423429 |
| 2. | McFadden E. R.Fatal and near fatal asthma. N. Engl. J. Med.3241991409411 |
| 3. | Sears M. R., Rea H. H.Patients at risk for dying of asthma: New Zealand experience. J. Allergy Clin. Immunol.801987477481 |
| 4. | Sly R. M.Mortality from asthma, 1979–1984. J. Allergy Clin. Immunol.821988705717 |
| 5. | Strunk R. C.Identification of the fatality-prone subject with asthma. J. Allergy Clin. Immunol.831989477485 |
| 6. | Barriot P., Riou B.Prevention of fatal asthma. Chest921987460466 |
| 7. | Stableforth, D. E. 1987. Asthma mortality and physician competence. J. Allergy Clin. Immunol. 80(3, Pt. 2):463–466. |
| 8. | Molfino N. A., Slutsky A. S.Near-fatal asthma. Eur. Respir. J.71994918990 |
| 9. | Blair H.Natural history of childhood asthma. Arch. Dis. Child.521977613619 |
| 10. | Sears M. R., Rea H. H., Beaglehole R., Gillies A. J. D., Holst P. E., O'Donnell T. V., Rothwell R. P. G., Sutherland D. C.Asthma mortality in New Zealand: a two year national study. N.Z. Med. J.981985271275 |
| 11. | Rubinfeld A. R., Pain M. C. F.Perception of asthma. Lancet11976882884 |
| 12. | Kikuchi Y., Okabe S., Tamura G., Hida W., Homma M., Shirato K., Takishima T.Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N. Engl. J. Med.330199413311334 |
| 13. | Borg G. A. V.Psychophysical bases of perceived exertion. Med. Sci. Sports Exerc.141982377381 |
| 14. | American Thoracic SocietyStandards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma (ATS statement). Am. Rev. Respir. Dis.1361987225244 |
| 15. | Jackson A. A., Milhorn H. T., Norman W. R.A reevaluation of the interrupter technique for airways resistance measurement. J. Appl. Physiol.361974264268 |
| 16. | Zechman, F. W., and R. L. Wiley. 1986. Afferent inputs to breathing: respiratory sensation. In N. S. Cherniack and J. G. Widdicombe, editors. Handbook of Physiology, Section 3: The Respiratory System. Vol. II: Control of Breathing. American Physiological Society, Bethesda, MD. 449–474. |
| 17. | Wiley R. L., Zechman F. W.Perception of added airflow resistance in humans. Respir. Physiol.219667387 |
| 18. | Killian K. J., Mahutte C. K., Campbell E. J. M.Magnitude scaling of externally added loads of breathing. Am. Rev. Respir. Dis.12319811215 |
| 19. | Bakers J. H. C. M., Tenney S. M.The perception of some sensations associated with breathing. Respir. Physiol.1019708592 |
| 20. | Lansing, R. W., and R. B. Banzett. 1996. Psychophysical methods in the study of respiratory sensation. In L. Adams and A. Guz, editors. Respiratory Sensation, Vol. 90: Lung Biology in Health and Disease. Marcel Dekker, New York. 69–100. |
| 21. | Turcotte H., Corbeil F., Boulet L.-P.Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges. Thorax451990914918 |
| 22. | Higgs, C. M. B., and G. Laszlo. 1996. Perception of asthma. In L. Adams and A. Guz, editors. Respiratory Sensation, Vol. 90: Lung Biology in Health and Disease. Marcel Dekker, New York. 285–309. |
| 23. | Hudgel D., Cooperson D. M., Kinsman R. A.Recognition of added resistive loads in asthma. Am. Rev. Respir. Dis.1261982121125 |
| 24. | Burki N. K., Mitchell K., Chaudhary B. A., Zechman F. W.The ability of asthmatics to detect added resistive loads. Am. Rev. Respir. Dis.11719787175 |
| 25. | Montessart J. M., Picardo C., Lloberas P., Serra J., Luengo M., August-Vidal A.Ability of asthmatics with and without respiratory arrest to detect added resistive loads. J. Asthma251988131135 |
