Respiratory Sensation and Ventilatory Mechanics during Induced Bronchoconstriction in Spontaneously Breathing Low Cervical Quadriplegia

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1 Respiratory Sensation and Ventilatory Mechanics during Induced Bronchoconstriction in Spontaneously Breathing Low Cervical Quadriplegia M. Diane Lougheed, John Flannery, Katherine A. Webb, and Denis E. O Donnell Respiratory Investigation Unit, Department of Medicine, Queen s University, Kingston, Ontario, Canada Intensity of dyspnea during induced bronchoconstriction in asthma is strongly related to the reduction in inspiratory capacity (IC) as a result of dynamic hyperinflation. To determine the role of rib cage and intercostal muscle afferents in symptom perception during bronchoconstriction, we measured the relationship between dyspnea intensity and IC during induced bronchoconstriction in six subjects with complete C4-C7 quadriplegia who did not require assisted ventilation. Spirometry, lung volumes, breathing pattern, esophageal pressure (Pes), and dyspnea intensity (Borg Scale) were measured during high-dose methacholine bronchoprovocation up to 256 mg/ml or a maximum change ( ) in FEV 1 of 50%. Contemporaneous control data from subjects with asthma (n 12) who had completed the same protocol were used for comparison. At maximum response in quadriplegia, FEV 1 decreased by L (62 4%predicted) (mean SEM), and IC decreased by L (30 4%predicted). Dyspnea at maximum response was rated moderate to severe : Borg The predominant qualitative respiratory sensations were inspiratory difficulty and unsatisfied inspiration. The best correlate of dyspnea (Borg) was IC (p ), whereas changes in FEV 1, Pes-derived measurements and breathing pattern did not contribute further to the strength of this relationship. Dyspnea intensity, quality, and changes in spirometry and lung volumes at maximum response were similar to those reported previously in asthma. The relationship between dyspnea intensity and IC was linear and consistent across groups. We conclude that the quality and intensity of dyspnea during methacholine-induced bronchoconstriction and dynamic hyperinflation was not altered by extensive chest wall deafferentation. Keywords: quadriplegia; asthma; bronchoconstriction; lung hyperinflation; dyspnea; methacholine challenge The intensity of dyspnea during induced bronchoconstriction in asthma is strongly related to a reduction in inspiratory capacity (IC) as a result of dynamic hyperinflation (1 3). We have previously shown that a major qualitative dimension of breathing discomfort during bronchconstriction in asthma is inspiratory difficulty, which encompasses a sense of unsatisfied inspiration (1, 2). The reduction in IC reflects mechanical volume restriction imposed on the respiratory system that is forced to operate at a high lung volume nearer total lung capacity (TLC). The mechanism by which dynamic hyperinflation causes respiratory discomfort is unknown and is likely multifactorial (4, 5). When the respiratory system is forced to operate at an (Received in original form September 4, 2001; accepted in final form April 30, 2002) Supported by Physicians Services Incorporated Foundation and the Ontario Thoracic Society. Correspondence and requests for reprints should be addressed to Dr. M. Diane Lougheed, 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. mdl@post. queensu.ca Am J Respir Crit Care Med Vol 166. pp , 2002 DOI: /rccm Internet address: end-expiratory lung volume (EELV) above its relaxation volume, the inspiratory muscles are burdened with increased elastic work in addition to increased resistive work due to bronchoconstriction (2). This results in a requirement for heightened inspiratory effort to maintain a given ventilation. The inspiratory muscles are also functionally weakened by altered length tension relationships, such that increased effort must be expended for a given force generation. Finally, dynamic hyperinflation restricts thoracic displacement and likely causes neuromechanical uncoupling of the respiratory system, which may contribute to the intensity and quality of dyspnea (2). It is postulated that dyspnea during acute bronchoconstriction is not only a function of the amplitude of central motor command output (and corollary discharge) but is also importantly modulated by peripheral feedback from a host of respiratory mechanoreceptors that provide precise kinesthetic information about inspiratory muscle displacement (muscle spindles), tension development (Golgi tendon organs), changes in respired volume and flow, and airway caliber (vagal lung and airway mechanoreceptors) (4). Corollary discharge refers to the transmission of signals from the motor cortex to the sensory cortex simultaneous to signals to contracting muscles (6). Bronchoconstriction is thought to activate slowly adapting pulmonary (stretch) receptors, rapidly adapting (irritant) receptors in the airway epithelium, and/or C-fibers (including J-receptors) in the airways and lung parenchyma. Presumably, receptors in the chest wall (rib cage and intercostal muscles), scalene and sternocleidomastoid muscles, and diaphragm are also activated during induced bronchoconstriction and hyperinflation and can contribute to the quality and intensity of respiratory sensations and discomfort or dyspnea (4). Binks and coworkers (7) recently reported that chest tightness during induced bronchoconstriction is not affected by reduced respiratory muscle activity during mechanical ventilation. However, the relative contribution of airway, chest wall, and diaphragmatic receptors to the perception of the intensity and quality of respiratory sensations in induced bronchoconstriction and hyperinflation is not known and has never previously been studied. Quadriplegic patients with complete mid-to-low cervical lesions are deprived of afferent information from the rib cage and intercostal muscles and lack sympathetic innervation of the lungs, although vagal parasympathetic innervation remains intact. Nonetheless, breathlessness in quadriplegia is common (8). Previous studies in patients with quadriplegia (9 15) and neuromuscular blockade (16 18) have helped elucidate the contribution of receptors in these denervated sites to various respiratory sensations. Studies have consistently shown that the perception of increased PCO 2, described most commonly as a sensation of air hunger, is preserved despite a lack of afferent input from rib cage receptors or respiratory muscle contraction (15 18). However, conflicting results have been reported regarding the role of chest wall receptors in the perception of external resistive and elastic loads and volume change. Although sensory detection thresholds during expiratory resistive loading

2 Lougheed, Flannery, Webb, et al.: Dyspnea and Hyperinflation in Quadriplegia 371 in quadriplegia are preserved, the quality of respiratory sensations differs from that of normal subjects (14). Detection thresholds for inspiratory resistive loading are impaired (increased) (9) and magnitude scaling of elastic and resistive loading is blunted (12) in quadriplegia, suggesting that chest wall receptors modulate the detection and intensity of respiratory sensations. Conversely, other studies have found detection thresholds (13) and magnitude estimation of volume (11) changes in quadriplegia were preserved. Yet tracheostomized patients with quadriplegia (15) and paralyzed normal subjects (17) reported variable sensations of the size of breath and air delivered during mechanical ventilation with constant ventilator settings, and normal subjects found dyspnea during CO 2 -loaded breathing less distressing while paralyzed (18). Extrinsic loading does not mimic the mechanical load encountered during spontaneous asthma (4), and previous studies have not thoroughly evaluated the intensity and quality of respiratory discomfort or dyspnea during intrinsic loading. Airway hyperresponsiveness to methacholine has previously been documented in quadriplegia (19). The existence of this phenomenon made it possible to evaluate sensory responses during intrinsic loading over a range of physiologic stimuli from minor bronchoconstriction to moderate dynamic hyperinflation in quadriplegia. We postulated that if sensory information from the chest wall mechanoreceptors were critically important for the ability to quantify and describe the qualitative aspects of respiratory discomfort during intrinsic mechanical loading, then sensory responses to bronchoconstriction would be different in patients with spinal cord injuries (SCIs) than in neurologically intact patients with asthma. We evaluated changes in operating lung volumes, breathing pattern responses, dyspnea (intensity and quality), and esophageal pressure derived measurements during bronchoprovocation in quadriplegic subjects. These data were compared with previously published data from contemporaneous control subjects with asthma who completed the same protocol (2). Finally, we examined physiologic parameters predictive of dyspnea in the quadriplegic group. METHODS Subjects We studied six fully rehabilitated, spontaneously breathing subjects with complete low cervical cord (C4-C7) quadriplegia (Table 1). SCI levels and completeness were based on the 1992 Revised American SCI Association (ASIA) classification (20). Subjects with quadriplegia had no pre- or postinjury asthma. Twelve previously studied subjects with asthma (2) who had undergone similar testing were used for comparison purposes. Subjects were excluded if they had a medical contraindication to methacholine challenge testing (21). Study Design Study approval was received from the university research ethics board. Subjects gave written informed consent before testing. After baseline assessments of spirometry, body plethysmography, maximal occlusion pressures, breathing pattern, esophageal pressure (Pes), and respiratory sensation, subjects underwent methacholine bronchoprovocation testing to a maximum change in FEV 1 of 50% from the lowest postsaline value or to symptom tolerance. All measurements were repeated after each dose of methacholine. After the maximum dose, the quality respiratory sensation was evaluated. Methacholine Challenge Testing Methacholine challenge tests were performed according to standardized protocols as previously described (1, 2). Although prior experience indicates that individuals with quadriplegia can compensate as well as neurologically intact individuals to resistive loading (14), the following extra safety precautions were taken: a physician was in attendance at all times; the test was terminated if dyspnea became severe (5 on the Borg Scale) or FEV 1 decreased to 0.5 L; the nebulizer was driven by compressed oxygen to avoid oxygen desaturation; blood pressure was measured after each dose of methacholine to detect an autonomic reaction; and nebulized salbutamol and ipratropium bromide were immediately available. Measurements Spirometry, body plethysmography, maximal occlusion pressures, breathing pattern, Pes, oxygen saturation (Sa O2 ), and respiratory sensation were collected as previously described (2) apart from the following measurements. Spirometry and body plethysmography were performed using a 6200 Autobox D L (SensorMedics, Yorba Linda, CA). Pes-derived measurements and breathing pattern were recorded continuously with a CP- 100 Pulmonary Monitor (BICORE Monitoring Systems, Irvine, CA). Dyspnea was defined for subjects as breathing discomfort. During bronchoprovocation, subjects used the modified Borg Scale (22) to rate the intensity of overall breathing discomfort, inspiratory difficulty ( difficulty breathing in ), and expiratory difficulty ( difficulty breathing out ). Immediately after measurements at maximum response were completed, subjects described their sensation of dyspnea by selecting as many representative descriptive phrases as they pleased from a list modified from that of Simon and coworkers (23). Statistical Analysis Results are expressed as means SEM. A statistical significance of 0.05 was used for all analyses, with the appropriate Bonferroni correction for multiple comparisons. Slopes were determined using linear regression analysis on individual data sets (24). Within-group comparisons were performed using paired t statistics. Unpaired t statistics were used for between-group comparisons. Pulmonary function measurements were standardized as % of predicted normal values (25, 26). Dyspnea descriptors were analyzed as frequency statistics and compared across groups using Fisher exact test. To determine factors associated with induced dyspnea, we used a multivariable linear model with change [ ] from baseline in the Borg TABLE 1. SUBJECT CHARACTERISTICS Subject No. Age (yr) Sex Height (cm) Weight (kg) BMI (kg/m 2 ) Duration of Injury (yr) Sensory Level Motor Level Neurologic Level* ASIA Impairment Scale 1 23 F C6 C6 C6 A 2 39 M C7 T1 C7 A 3 22 M C5 C5 C5 A 4 41 M C4 C6 C4 A 5 35 M C5 C5 C5 A 6 30 M C5 C4 C4 A Mean SEM Definition of abbreviations: ASIA American Spinal Injury Association; BMI body mass index. * Most quadriplegic subjects had partial function (zone of partial preservation of innervation) for one to two levels below the neurologic level.

3 372 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. BASELINE PULMONARY FUNCTION AND AIRWAY RESPONSIVENESS IN QUADRIPLEGIC SUBJECTS FEV 1, L FEV 1 /FVC, % FVC, L FRC, L TLC, L RV, L PC 20 (mg/ml) (60) 90 (113) 2.53 (53) 1.77 (49) 3.71 (54) 1.44 (69) (80) 87 (114) 3.52 (71) 2.10 (55) 4.79 (69) 1.20 (61) (44) 88 (108) 2.11 (41) 2.79 (78) 4.68 (70) 2.36 (153) (57) 74 (96) 2.76 (59) 2.76 (78) 4.97 (76) 2.18 (117) (65) 82 (107) 3.26 (61) 3.59 (88) 6.32 (85) 3.17 (156) (40) 93 (119) 1.83 (34) 2.66 (67) 4.51 (63) 2.68 (144) 15.3 Mean 2.27 (57) 85 (110) 2.67 (53) 2.61 (69) 4.83 (72) 2.16 (118) 7.8 SEM 0.21 (6) 3 (3) 0.27 (6) 0.26 (6) 0.35 (5) 0.32 (19) 3.0 Definition of abbreviations: PC 20 provocation dose where FEV 1 had decreased by 20% from baseline; RV residual volume. Scale as the dependent variable and concurrent changes in relevant spirometric parameters, operational lung volumes, breathing pattern, and Pes-derived measurements as candidate independent variables. Due to dependency between serial measurements within subjects, subjects (categorical variable) were treated as random effects in the regression model. The relationship between induced dyspnea and the strongest independent variable(s) within the quadriplegic group was compared with a similar model in individuals with asthma by incorporating the interaction term with group into the model. RESULTS Subject Characteristics Demographics, SCI levels, and baseline pulmonary function are outlined in Tables 1 and 2. Two subjects were current smokers and two were ex-smokers. Two subjects were taking baclofen, which is known to decrease airway responsiveness (27). Subjects with quadriplegia were similar in age, height, body mass index (BMI), and FEV 1 /FVC to a previously studied group of subjects with asthma with normal baseline pulmonary function, breathing pattern, and respiratory mechanics (2). Subjects with quadriplegia demonstrated mild to moderate restriction (Table 2), mildly reduced maximal inspiratory mouth occlusion pressures (90 14 cm H 2 O, 79 16%predicted), and significantly reduced maximal expiratory mouth occlusion pressures (86 7 cm H 2 O, 41 7%predicted). Steady-state ventilation (VE), tidal volume (VT), and tidal flow rates were normal in quadriplegia, with a tendency for prolonged expiration (TE) resulting in a relatively shortened duty cycle (TI/Ttot) (see baseline data in Table 3). An increased tidal Pes/VT ratio was consistent with restrictive mechanics (Table 3). Physiologic Responses to Methacholine The only adverse reaction to methacholine was a transient autonomic headache in one subject, which resolved with sublin- TABLE 3. BASELINE AND MAXIMUM RESPONSE TO METHACHOLINE CHALLENGE IN QUADRIPLEGIA (n 6) Baseline Maximum Change Dyspnea, Borg Scale * Inspiratory difficulty, Borg * Expiratory difficulty, Borg * Pulmonary function FEV 1, L * FEV 1, %predicted * 36 5 FEV 1 /FVC, %predicted * 34 3 FVC, %predicted * 24 4 IC, %predicted * 30 4 ERV, %predicted TLC, %predicted RV, %predicted * FRC, %predicted * 34 6 Breathing pattern & operating lung volumes VE, L/min VT, L f, breaths/min TI, s TE, s IC, L * EILV/TLC, % * 18 3 Respiratory mechanics Tidal Pes, cm H 2 O Tidal Pes/VT, cm H 2 O/L Pes/PI max :VT/predicted VC CL dyn, L/cm H 2 O PI max, cm H 2 O AutoPEEP, cm H 2 O TTI, mean Pes/PI max TI/Ttot Definition of abbreviations: autopeep intrinsic positive end-expiratory pressure; CL dyn dynamic compliance; EILV end-inspiratory lung volume; ERV expiratory reserve volume; f respiratory frequency; IC inspiratory capacity; Pes esophageal pressure; PI max maximal inspiratory pressure; RV residual volume; TE expiratory time; TI inspiratory time; TTI tension time index. Values are means SEM. * Different from baseline using a p 0.05 level of significance and the Bonferroni correction for multiple comparisons.

4 Lougheed, Flannery, Webb, et al.: Dyspnea and Hyperinflation in Quadriplegia 373 Figure 1. Tidal and maximal flow volume loops are shown at baseline (solid lines) and at the maximum response (dashed lines) to methacholine bronchoprovocation in subjects with asthma (n 12) and quadriplegia (n 6). Predicted maximal expiratory flow volume curves are also shown (dotted lines). Curves are constructed from mean flow and volume parameters within each group. TLC total lung capacity; RV residual volume. Figure 3. Changes from baseline to maximum response are shown for various breathing pattern parameters in subjects with asthma (shaded bars) and in those with quadriplegia (solid bars). *p 0.05 significant change from baseline. VE minute ventilation; VT tidal volume; F breathing frequency; TI inspiratory time; TE expiratory time; TI/ Ttot inspiratory duty cycle; VT/TI mean inspiratory flow rate; VT/TE mean expiratory flow rate. gual nifedipine (10 mg). There were no significant changes in systolic or diastolic blood pressure from baseline to maximum response. No arterial desaturation occurred during testing. Quadriplegic subjects had mildly increased mean airway responsiveness, as measured by the provocation dose where FEV 1 had decreased by 20% from baseline (PC 20 ) (Table 2) and reached a maximum dose of methacholine of mg/ ml. Maximal responses to methacholine in the subjects with quadriplegia are summarized in Table 3. From baseline to maximum response, FEV 1 fell by L (62 4%) in subjects with quadriplegia (p 0.001). Five out of six subjects with quadriplegia showed significant expiratory flow limitation at maximum response, i.e., tidal expiratory flows overlapped the maximal expiratory flow volume envelope (Figure 1). Lung volumes. (Figure 2, Table 3) From baseline to maximum response in subjects with quadriplegia, IC decreased by L (30 4%predicted) (p 0.001) and FRC increased by L (p 0.001), with a resultant increase in TLC of L (p 0.10). Breathing pattern. (Figure 3, Table 3) In the group with quadriplegia, TE shortened (p 0.05) and breathing pattern became more rapid (p 0.05) and shallow (p 0.06) from baseline to maximum response. Respiratory mechanics. Changes in Pes-derived mechanical measurements are provided in Table 3. At maximum response in subjects with quadriplegia, Pes/VT ratios increased significantly (p 0.05), but increases in respiratory effort (tidal Pes/PI max ), work of breathing, and the pressure time product did not reach statistical significance. PI max did not change significantly during induced bronchoconstriction. Respiratory Sensation From a mean baseline Borg rating of or none at all, dyspnea intensity increased significantly (p 0.001) during bronchoprovocation: Borg ratings reached somewhat severe in subjects with quadriplegia at maximum response. As in the subjects with asthma at maximum response, Borg ratings of inspiratory difficulty were significantly greater than expiratory difficulty in subjects with quadriplegia (Table 3). Figure 2. Operational lung volumes at baseline, near PC 20 and at maximum response to methacholine are shown in subjects with asthma (n 12) and quadriplegia (n 6). In the group with asthma, it was assumed that TLC did not change during bronchoconstriction (1). IC inspiratory capacity; IRV inspiratory reserve volume; ERV expiratory reserve volume; RV residual volume; PC 20 provocation dose where FEV 1 had decreased by 20% from baseline. Figure 4. Descriptors of dyspnea at maximum response during bronchoprovocation are similar in asthma (n 12; shaded bars) and quadriplegia (n 6; solid bars).

5 374 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL The frequency of selection of qualitative descriptors of breathing discomfort was not significantly different between groups (Figure 4). However, the sense of chest tightness tended to occur less often (p 0.08) and the feeling of rapid breathing tended to occur more often (p 0.14) in subjects with quadriplegia than in subjects with asthma. Figure 5 shows the relationships between dyspnea intensity (Borg Scale) and changes ( ) in each of FEV 1 and IC. Slopes of Borg dyspnea ratings against both FEV 1 %predicted and IC%predicted were linear and similar in asthma and quadriplegia. However, when FEV 1 was expressed as a percentage of fall from baseline, dyspnea/ FEV 1 slopes were somewhat greater in asthma than quadriplegia (p 0.07). Within subjects with quadriplegia, IC%predicted was the strongest significant correlate of dyspnea intensity (Borg or Borg) during progressive bronchoconstriction (partial r , p ). After accounting for the IC%predicted, changes in other variables including FEV 1 %predicted, the FEV 1 /FVC ratios, Pes-derived mechanical measurements (including Pes/PI max and Pes/VT ratios), and breathing pattern parameters (including timing, flow, and volume measurements) did not contribute significantly to the variance in Borg dyspnea ratings. DISCUSSION This study confirmed the previous report (19) that subjects with quadriplegia with no clinical history of asthma before or after spinal cord transection display airway hyperresponsiveness comparable with mild asthma. This is the first study to demonstrate that subjects with quadriplegia experience dyspnea during bronchoconstriction, which is qualitatively similar to that experienced by neurologically intact subjects with asthma. Furthermore, the relationship between the change in IC and change in dyspnea is fully preserved in quadriplegia during bronchoconstriction despite substantial rib cage, intercostal muscle, and sympathetic deafferentation, baseline restrictive mechanics, different breathing pattern responses to methacholine, and limited expiratory muscle force-generating capacity. The neurologic impairment of the subjects with quadriplegia in this study was determined by a physician (J. F.) experienced in the use of the ASIA standards for classification of SCI. These standards represent the most valid, precise, and reliable method of evaluating and reporting SCI severity (20, 28). The degree of neurologic impairment was complete in all the subjects with quadriplegia in this study (i.e., there was no sensory or motor function in the lowest sacral segments). Sensory levels ranged from C4 to C7, with the lowest zone of partial preservation of T1 (n 1). Motor levels ranged from C5 to T1, with the lowest zone of partial preservation of T1 (n 1). Thus, our subjects lacked substantial chest wall sensation, had reduced sympathetic innervation of the lung, had complete paralysis of the main expiratory muscles (abdominal muscles and internal intercostals), and varying degrees of denervation of the major muscles of inspiration: the diaphragm (C3 C5), scalene muscles (C4 C8), and intercostal muscles (T1 T12). Despite paralysis of the major expiratory muscles, subjects with quadriplegia performed repeated forced expiratory maneuvers which met published acceptability criteria (29). Active expiration in subjects with quadriplegia was presumably aided by contraction of pectoralis major (30). The moderate restrictive defects in the subjects with quadriplegia in this study are consistent with previous reports in this patient population (31, 32). They demonstrated reduced static lung volumes (including ERV) and adopted a relatively shallow breathing pattern, in keeping with the mechanical derangements typical of quadriplegia, including reduced chest wall compliance and reduced static lung compliance (31, 32). Pes/VT ratios at baseline were increased in quadriplegia compared with asthma, suggesting increased dynamic elastance. We and others have previously outlined the mechanical changes which occur during methacholine-induced bronchoconstriction in asthma (1, 2, 33, 34). The inciting physiologic abnormality during bronchoconstriction is an increase in airway resistance due to bronchoconstriction. Dynamic increases in EELV ensue, due to expiratory flow limitation and/or inspiratory muscle braking during expiration (34, 35). As EELV increases (and IC decreases), end-inspiratory lung volume (EILV) migrates closer to TLC, IRV decreases, the VT/IC and EILV/ TLC ratios increase, and VT becomes positioned on a stiffer portion of the pressure volume relationship of the respiratory system (1, 2, 33). As a result of these functionally restrictive mechanics, elastic and inspiratory threshold loads ensue, the inspiratory muscles are functionally weakened by altered length Figure 5. Relationships between dyspnea intensity (Borg) and change in inspiratory capacity (IC) or change in FEV 1 (each expressed as % of predicted normal) during methacholine-induced bronchoconstriction were similar in quadriplegia (Q) (n 6) and asthma (A) (n 12). When the change in FEV 1 was expressed as % fall from baseline, slopes were slightly greater in subjects with asthma than in those with quadriplegia (p 0.07) due to bias from differences in group baseline measurements. Values shown are means SEM.

6 Lougheed, Flannery, Webb, et al.: Dyspnea and Hyperinflation in Quadriplegia 375 tension relationships, and the ratio of respiratory effort (Pes/ PI max ) to the VT response increases (2). Resting breathing pattern and timing components were significantly different in subjects with quadriplegia and those with asthma at baseline TI/Ttot was shorter and TE was relatively increased in subjects with quadriplegia. The smaller increase in tidal Pes and in the tidal Pes VT ratio during bronchoconstriction in subjects with quadriplegia compared with subjects with asthma reflects differences in baseline mechanics together with the relatively shallow and rapid breathing response to bronchoconstriction in subjects with quadriplegia, which minimized inspiratory pleural pressure swings. In addition, Pes measurements in quadriplegia may underestimate true neuromotor output because of chest wall distortion. Lung volume measurement by constant volume plethysmography (36) is unlikely to be affected by abdominal gas compression in quadriplegia due to paralysis of the major expiratory muscles. However, the potential to overestimate FRC during bronchoconstriction if panting frequency is not standardized still exists (37). We have previously demonstrated that IC reflects FRC during bronchoconstriction in asthma when panting frequency is standardized and TLC remains constant (1). The change in FRC exceeded the change in IC in subjects with quadriplegia by almost 400 ml. We postulate that this difference was due to the recognized limitations of the Dubois method of body plethsymography during bronchoconstriction (36), rather than reduction in IC due to increased airway resistance or functional inspiratory muscle weakness, as PI max remained unchanged. Of note, the calculated change in TLC (FRC plus IC) from baseline to maximal response in quadriplegia did not reach statistical significance. For graphic calculations, tidal and maximal flow volume curves were positioned on the volume axis according to TLC. Substantial reductions in IC occurred in both groups, and despite the potentially artifactual increase in TLC in quadriplegia, VT became positioned closer to TLC and the upper alinear extreme of the respiratory system s pressure volume relationship in both groups. Martin and coworkers (34) have previously shown that the external intercostals have an important role in braking. Given extensive chest wall denervation and paralysis of the intercostal muscles, the increase in EELV in subjects with quadriplegia was not likely due to active inspiratory muscle braking. Expiratory flow limitation, as suggested by the overlap of tidal expiratory flow and the maximal expiratory flow envelope, was present in five out of six patients with quadriplegia at maximal response, and is the most likely mechanism of DH. If one were only to examine the relationship between change in Borg dyspnea ratings and % fall in FEV 1.0 during bronchoconstriction, one might erroneously conclude that individuals with quadriplegia have relatively blunted sensory responses or were more stoic. However, when differences in baseline mechanics between the two groups were taken into account, we see that sensory responses to a given stimulus were actually well preserved in subjects with quadriplegia. Dyspnea rating/ IC and dyspnea rating/ FEV 1.0 plots were superimposed in subjects with quadriplegia and in those with asthma when these physiologic variables were expressed as %predicted. We suspect that the lower peak value of dyspnea in subjects with quadriplegia reflected limiting restrictive mechanics and, therefore, a smaller change in IC at peak bronchoconstriction. As we have previously reported in individuals with asthma (1, 2), the change in IC also emerged as the strongest correlate of induced dyspnea in individuals with quadriplegia (explaining over 50% of the variance). The addition of the change in FEV 1.0, inspiratory effort, and breathing pattern to the change in IC in the multivariable linear model did not add to the strength of this relationship. Descriptors of respiratory discomfort, which allude to inspiratory difficulty and unsatisfied inspiration (selected at peak bronchoconstriction), were similar between groups. This is consistent with previous reports that although physicians generally think asthma is characterized by expiratory difficulty (38), patients report experiencing inspiratory difficulty during spontaneous and induced bronchoconstriction (1, 2, 38). The neurophysiologic underpinnings of these distinct qualitative components of dyspnea remain unknown. Because these discrete descriptors can be reproduced in healthy individuals by the imposition of chest wall strapping and ventilatory stimulation (i.e., added deadspace) at a given metabolic load, we have postulated that disparity between central corollary discharge and the simultaneous mechanical response (i.e., thoracic displacement) may represent one underlying mechanism of perceived unsatisfied inspiration (39). This disparity is termed neuromechanical uncoupling or dissociation (4). Afferents from the chest wall (rib cage and associated musculature) and diaphragm are uniquely positioned to provide precise sensory information related to inspiratory muscle tension development during mechanical loading and may be the proximate source of volume feedback information (40). Based on previous studies in patients with quadriplegia patients, chest wall afferents are not essential for the detection and magnitude estimation of added resistive loads to breathing (9, 16). However, one study showed impairment in the ability to scale the magnitude of added elastic loads (10). Similarly, Gottfried and coworkers (12) showed that magnitude scaling of submaximal elastic and resistive loads (applied for a few breaths) was impaired in subjects with low cervical cord quadriplegia compared with healthy control subjects. Our study, which has examined sensory responses to a range of physiologic stimuli during progressive bronchoconstriction, is not directly comparable to previous studies using external mechanical loading: externally applied loads poorly simulate events during bronchoconstriction, particularly expiratory flow limitation and its mechanical consequence (41). Moreover, previous studies have not accounted for differences in baseline ventilatory mechanics, changes in lung hyperinflation during loading, or alterations in breathing pattern during sustained, progressive loading. It is reasonable to assume that individuals with quadriplegia, deprived of specific sensory inputs from the chest wall, may rely to a greater extent on vagal afferent inputs to convey information about lung volume changes relative to central motor command output. Banzett and colleagues (13) have previously shown that the sensation of respiratory displacement is preserved in quadriplegia. Subsequently, Manning and coworkers (42) demonstrated that vagal pulmonary afferents can modulate dyspnea (airhunger). Information about thoracic displacement and muscle tension development may be mediated through mechanoreceptors in the diaphragm because it is known that afferent information from both muscle spindles and golgi tendon organs travels via the phrenic nerves (16). In addition, accessory respiratory muscle activation during acute loading may contribute to respiratory sensations. An alternative hypothesis, which we feel is less likely, is that the intensity and quality of dyspnea during methacholine bronchoprovocation is directly related to sensory perturbations as a result of acute bronchospasm. Clearly, there are multiple and parallel afferent pathways that provide considerable redundancy in neurosensory inputs. Our results by no means obviate the possibility that chest wall receptors normally contribute to dyspnea during bronchoconstriction in individuals with asthma. They do, however, suggest that a relatively limited

7 376 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL pool of sensory neurons, whose afferent inputs travel via the vagus and phrenic nerves, can evoke complex respiratory sensations which, either directly or indirectly, can contribute to respiratory discomfort during bronchoconstriction. In summary, reduction in IC, reflecting dynamic increase in EELV, was the most important physiologic parameter associated with the intensity of induced dyspnea during moderateto-severe acute bronchoconstriction in quadriplegia. Discomfort that arose from being forced to breathe at lung volumes above the respiratory system s relaxation volume in quadriplegia was perceived to be of comparable intensity as that experienced by individuals with asthma for a given change in IC. In quadriplegia, breathing discomfort was also qualitatively similar to that in asthma at maximal response. 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