How Does Baseline Airway Tone Modulate Bronchodilation During A Deep Inhalation? D.A. AFFONCE 1 , A. GARRISON 2 , L.D. BLACK 1 , J.J. FREDBERG 3 , R. BROWN 4 , E. GARSHICK 2 AND K. LUTCHEN 1 1 Boston University, Boston, MA; 2 VA Boston Healthcare System, Boston, MA; 3 Harvard University, Boston, MA; 4 Massachusetts General Hospital, Boston, MA Background •During a deep inspiration (DI) healthy people have a greater ability to dilate their airways, even after a bronchial challenge when compared to asthmatics (1,2) •Non asthmatic subjects with cervical spinal cord injury (SCI) have been shown to be hyperreactive to methacholine (MCh) (3,4,5) Goal To test the hypothesis that subjects that have been found to have enhanced airway hyperreactivity (e.g. asthmatics and SCI subjects) also have a distinct relationship between baseline airway tone, as measured by respiratory system resistance (R rs ) and there ability to dilate their airways with a DI Methods • Airway tone was measured as R rs at 8 Hz • To measure R rs @8 Hz an 8 Hz oscillation is super imposed over a person’s spontaneous breathing •The acquired airway opening pressure and flow signals are then high passed filtered with a 4 pole Butterworth filter with a 4 Hz corner frequency • The R rs was then calculated by plugging the isolated 8 Hz pressure and flow signals into the following set of equations: 0 ao l ao l ao P dt V E V R P cw t aw l R R R R FRC) Volume 0, (V P P ao ao 0 • Black et. al. have shown that R rs at TLC is indicative of maximum airway caliber FIGURE 1: System Diagram Protocol •6 healthy pre and post bronchial challenge, 10 asthmatics pre and post bronchial challenge, and 22 SCI (8 Cervical, 7 Thoracic, and 7 Lumbar) subjects have been tested •Subject is told to take 5 tidal breaths followed by a DI to TLC and then to return to tidal breathing for 5 more breaths Results •Healthy subjects at baseline have the least airway tone. When challenged healthy subjects airway tone approached that of baseline asthmatics. All SCI subjects had airway tones that were similar to that of baseline asthmatics. Baseli ne Post Challenge Baseli ne Post Challenge All SCI Cervical SCI Thoracic SCI Lumbar SCI Figure3 Airway tone as measured by R rs for each subject group • Healthy subjects at baseline again have the smallest R min , or the greatest ability to maximally dilate airways . Healthy subjects post challenge have a value slightly higher R min than that at baseline, but less than those of asthmatics and baseline, even though their airway tone was the same to start. Asthmatics and SCI subjects show a distinct defect in their ability to dilate their airways by taking a deep breath, independent of injury level in SCI. Baseli ne Post Challenge Baseli ne Post Challenge All SCI Cervical SCI Thoracic SCI Lumbar SCI Figure 4 R min for each subject group (see fig. 2) •Note how the SCI subjects and asthmatic subjects have similar correlations of R min and ΔR as a function of R rs and this correlation is markedly different from that of healthy subjects. It should also be noted that neither ΔR or R min correlate with IC or FEV 1 . Using FEV 1 data and R min you can differentiate between healthy and asthmatic subjects. However this is not possible in SCI subjects have significantly lower FEV 1 values because of their low IC. Figure 6 R min and ΔR as a function of R rs ,IC, and FEV 1 % predicted •Healthy people at baseline have the highest IC but only slightly higher then PC healthy or baseline asthmatics. With SCI subjects IC became larger as the level of injury was further down the spine, as expected. However subjects with cervical SCI, who had the lowest IC, did not have the higher R min Figure 5 IC for each group of subjects Baseli ne Post Challenge Baseli ne Post Challenge All SCI Cervical SCI Thoracic SCI Lumbar SCI Discussion •When healthy subjects are challenged to elevate their baseline airway tones to that of Asthmatic subjects and SCI subjects, they still maintain the ability to maximally dilate their airways. Whereas asthmatics and subjects with SCI both have a similar inability to dilate their airways •Although subjects with asthma have a diminished IC when compared to healthy subjects there was no correlation between IC and R min . Also past studies (1) have shown that asthmatics generate nearly the same transpulmonary pressures as healthy subjects. Hence their inability to maximally dilate their airways is a direct result of a defect in the airway wall and/or airway smooth muscle •Although subjects with cervical SCI have the lowest IC they do not have the highest R min which means that the inability of subjects with SCI to bronchodilate during a DI is not caused by insufficient local tethering forces. It is most likely caused by an inability to generate sufficient transpulmonary pressure or there is a defect at the level of the airway walls and/or smooth muscle Figure 2 Raw data for 2 SCI subjects with thoracic injuries, note the difference in IC but not in R min R min Summary •Subject groups in which enhanced airway hyperreactivity is reported also show a depressed ability to maximally dilate there airway in a manner distinct from healthy subjects both before and after bronchial challenge •The primary force controlling maximal dilation does not appear to be parenchyma tethering associated with local volume expansion. The primary force is more likely a function of maximal elastic recoil pressure and airway smooth muscle stiffness •Current and past data indicate that smooth muscle is the primary culprit in asthma. However in SCI it is unclear whether it is smooth muscle or loss of elastic recoil pressure •Future studies should measure elastic recoil pressure during the same maneuvers and also test the reactivity of each subject group explicitly 1 A. Jensen, H. Atileh, B. Suki, E. Ingenito, and K. Lutchen. Airway Caliber in Healthy and Asthmatic Subjects: Effects of Bronchial Challenge and Deep Inspiration. J Appl Physiol 2001 96:506-515 2 L. Black, R. Dellaca, K. Jung, H. Atileh, E. Israel, E. Ingenito, and K. Lutchen. Tracking Variations in Airway Caliber by Using Total Respiratory Vs. Airway Resistance in Healthy and Asthmatic Subjects. J. Appl Physiol 2003 95:511-518 3 E. Singas, M. Lesser, A. Spungen, W. Bauman, and P Almenoff. Airway Hyperresponsiveness to Methacholine in Subjects With Spinal Cord Injury. Chest Oct. 1996 110(4):911-915 4 P. Dicpinigaitis, A. Spungen, W. Bauman, A. Absgarten, and P. Almenoff. Bronchial Hyperresponsiveness After Cervical Spinal Cord Injury. Chest April 1994 109(4):1073-1076 5 D. Grimm, R. DeLuca, M. Lesser, W. Bauman, and P. Almenoff. Effects of GABA-B Agonist Baclofen on Bronchial Hyperreactivity to Inhaled Histamine in Subjects with Dervical Spinal Cord Injury. Lung 1997 175:333-341 References Supported by NIH HLB 62269, the DVA Cooperative Studies Program and NIH R01 HD42141 * p<0.05 when compared to healthy at baseline * * * * * * * * * * * * * * * * *
How Does Baseline Airway Tone Modulate Bronchodilation During A Deep Inhalation? D.A. AFFONCE 1, A. GARRISON 2, L.D. BLACK 1, J.J. FREDBERG 3, R. BROWN.
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How Does Baseline Airway Tone Modulate Bronchodilation During A Deep Inhalation?
D.A. AFFONCE1, A. GARRISON2, L.D. BLACK1, J.J. FREDBERG3, R. BROWN4, E. GARSHICK2 AND K. LUTCHEN1
1Boston University, Boston, MA; 2VA Boston Healthcare System, Boston, MA; 3Harvard University, Boston, MA; 4Massachusetts General Hospital, Boston, MA
Background•During a deep inspiration (DI) healthy people have a greater ability to dilate their airways, even after a bronchial challenge when compared to asthmatics (1,2)
•Non asthmatic subjects with cervical spinal cord injury (SCI) have been shown to be hyperreactive to methacholine (MCh) (3,4,5)
GoalTo test the hypothesis that subjects that have been found to have enhanced airway hyperreactivity (e.g. asthmatics and SCI subjects) also have a distinct relationship between baseline airway tone, as measured by respiratory system resistance (Rrs) and there ability to dilate their airways with a DI
Methods•Airway tone was measured as Rrs at 8 Hz
•To measure Rrs@8 Hz an 8 Hz oscillation is super imposed over a person’s spontaneous breathing•The acquired airway opening pressure and flow signals are then high passed filtered with a 4 pole Butterworth filter with a 4 Hz corner frequency•The Rrs was then calculated by plugging the isolated 8 Hz pressure and flow signals into the following set of equations:
0aolaolao PdtVEVRP
cwtawl RRRR FRC)Volume0,(VPP aoao0 •Black et. al. have shown that Rrs at TLC is indicative of maximum airway caliber
FIGURE 1:System Diagram
Protocol•6 healthy pre and post bronchial challenge, 10 asthmatics pre and post bronchial challenge, and 22 SCI (8 Cervical, 7 Thoracic, and 7 Lumbar) subjects have been tested
•Subject is told to take 5 tidal breaths followed by a DI to TLC and then to return to tidal breathing for 5 more breaths
Results
•Healthy subjects at baseline have the least airway tone. When challenged healthy subjects airway tone approached that of baseline asthmatics. All SCI subjects had airway tones that were similar to that of baseline asthmatics.
Baselin
e
Post
Challenge
Baseline
Post
Challenge A
ll SC
I
Cervical S
CI
Thoracic
SC
I
Lumbar S
CI
Figure3 Airway tone as measured by Rrs for each subject group
• Healthy subjects at baseline again have the smallest Rmin, or the greatest ability to maximally dilate airways . Healthy subjects post challenge have a value slightly higher Rmin than that at baseline, but less than those of asthmatics and baseline, even though their airway tone was the same to start. Asthmatics and SCI subjects show a distinct defect in their ability to dilate their airways by taking a deep breath, independent of injury level in SCI.
Baselin
e
Post
Challenge
Baseline
Post
Challenge A
ll SC
I
Cervical S
CI
Thoracic
SC
I
Lumbar S
CI
Figure 4 Rmin for each subject group (see fig. 2)
•Note how the SCI subjects and asthmatic subjects have similar correlations of Rmin and ΔR as a function of Rrs and this correlation is markedly different from that of healthy subjects. It should also be noted that neither ΔR or Rmin correlate with IC or FEV1. Using FEV1 data and Rmin you can differentiate between healthy and asthmatic subjects. However this is not possible in SCI subjects have significantly lower FEV1 values because of their low IC.
Figure 6 Rmin and ΔR as a function of Rrs,IC, and FEV1 % predicted
•Healthy people at baseline have the highest IC but only slightly higher then PC healthy or baseline asthmatics. With SCI subjects IC became larger as the level of injury was further down the spine, as expected. However subjects with cervical SCI, who had the lowest IC, did not have the higher Rmin
Figure 5 IC for each group of subjects
Baselin
e
Post
Challenge
Baseline
Post
Challenge A
ll SC
I
Cervical
SC
I
Thoracic
SC
I
Lumbar S
CI
Discussion
•When healthy subjects are challenged to elevate their baseline airway tones to that of Asthmatic subjects and SCI subjects, they still maintain the ability to maximally dilate their airways. Whereas asthmatics and subjects with SCI both have a similar inability to dilate their airways
•Although subjects with asthma have a diminished IC when compared to healthy subjects there was no correlation between IC and Rmin. Also past studies (1) have shown that asthmatics generate nearly the same transpulmonary pressures as healthy subjects. Hence their inability to maximally dilate their airways is a direct result of a defect in the airway wall and/or airway smooth muscle
•Although subjects with cervical SCI have the lowest IC they do not have the highest Rmin which means that the inability of subjects with SCI to bronchodilate during a DI is not caused by insufficient local tethering forces. It is most likely caused by an inability to generate sufficient transpulmonary pressure or there is a defect at the level of the airway walls and/or smooth muscle
Figure 2 Raw data for 2 SCI subjects with thoracic injuries, note the difference in IC but not in Rmin
Rmin
Summary
•Subject groups in which enhanced airway hyperreactivity is reported also show a depressed ability to maximally dilate there airway in a manner distinct from healthy subjects both before and after bronchial challenge
•The primary force controlling maximal dilation does not appear to be parenchyma tethering associated with local volume expansion. The primary force is more likely a function of maximal elastic recoil pressure and airway smooth muscle stiffness
•Current and past data indicate that smooth muscle is the primary culprit in asthma. However in SCI it is unclear whether it is smooth muscle or loss of elastic recoil pressure
•Future studies should measure elastic recoil pressure during the same maneuvers and also test the reactivity of each subject group explicitly
1 A. Jensen, H. Atileh, B. Suki, E. Ingenito, and K. Lutchen. Airway Caliber in Healthy and Asthmatic Subjects: Effects of Bronchial Challenge and Deep Inspiration. J Appl Physiol 2001 96:506-515
2 L. Black, R. Dellaca, K. Jung, H. Atileh, E. Israel, E. Ingenito, and K. Lutchen. Tracking Variations in Airway Caliber by Using Total Respiratory Vs. Airway Resistance in Healthy and Asthmatic Subjects. J. Appl Physiol 2003 95:511-518
3 E. Singas, M. Lesser, A. Spungen, W. Bauman, and P Almenoff. Airway Hyperresponsiveness to Methacholine in Subjects With Spinal Cord Injury. Chest Oct. 1996 110(4):911-915
4 P. Dicpinigaitis, A. Spungen, W. Bauman, A. Absgarten, and P. Almenoff. Bronchial Hyperresponsiveness After Cervical Spinal Cord Injury. Chest April 1994 109(4):1073-1076
5 D. Grimm, R. DeLuca, M. Lesser, W. Bauman, and P. Almenoff. Effects of GABA-B Agonist Baclofen on Bronchial Hyperreactivity to Inhaled Histamine in Subjects with Dervical Spinal Cord Injury. Lung 1997 175:333-341
References
Supported by NIH HLB 62269, the DVA Cooperative Studies Program and NIH R01 HD42141
* p<0.05 when compared to healthy at baseline
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