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

1
Does Ability to Maximally Dilate Airways Relate
to Airway Tone and Inspiratory Capacity in
Subjects with Hyperreactivity?
D.A. AFFONCE1, R. BROWN2,4, J.J. FREDBERG3, E.
GARSHICK4, AND K. LUTCHEN1 1Boston University,
Boston, MA 2Massachusetts General Hospital,
Boston, MA 3Harvard University, Boston, MA 4VA
Boston Healthcare System, Boston, MA
Results
Background

• Healthy people have a greater ability to dilate
  their airways with a deep inspiration (DI), 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)
• Subjects with high SCI do not sigh as often as
  healthy subjects (6) and likely have smaller
  tidal volumes. Therefore their ASM likely
  experience less stretch.

Baseline
Post Challenge
Baseline
Post Challenge
Goal
All SCI
Cervical SCI
Thoracic SCI
Lumbar SCI
Baseline Post Ipatroprium
Bromide
Baseline Post Ipatroprium
Bromide

• To determine how airway dilation ability in
  subject types with hyperreactivity relates to
  ability to modulate airway tone and lung volume
  as reflected in respiratory resistance and
  inspiratory capacity.

Figure 7 Effects of Ipatroprium Bromide on Rmin
an Rrs

• When ipatroprium bromide is administered to
  subjects with SCI it had no effect on their
  ability to dilate their airways.

Healthy Asthma SCI
Methods
Figure 4 Tidal Volume and Inspiratory Capacity
Discussion

• Rrs at 8 Hz reflects primarily airway resistance
• Changes in airway tone were reflected via
  changes in Rrs
• To measure Rrs_at_8 Hz an 8 Hz oscillation is super
  imposed over a persons spontaneous breathing.
  The acquired airway opening pressure and flow
  signals are then high passed filtered. Then the
  following equations are applied via a recursive
  least squares algorithm

• Healthy people at baseline have the highest IC
  and it was not significantly reduced post
  challenge (paired T test pgt0.1).
• Asthmatics have a significantly reduced IC
  compared to healthy subjects. It is even lower
  after challenge.
• SCI subjects as a group had a lower IC than
  healthy subjects, however when separated out by
  group only subjects with cervical injuries had a
  significant reduction in IC. All subjects groups
  have a similar tidal volume except for subjects
  with cervical SCI who have a reduced VT

• Healthy subjects challenged to produce
  elevations in Rrs (i.e. airway tone) to that of
  Asthmatic subjects, still maintain the ability to
  nearly maximally dilate their airways.
• Asthmatic and SCI subjects have a similar
  inability to dilate their airways.
• There is a trend for Rmin to be more elevated for
  higher injury levels
• Although subjects with asthma have a diminished
  IC when compared to healthy subjects there was
  no correlation between IC and Rmin. These
  asthmatics were able to generate transpulmonary
  pressures that were similar to the healthy
  subjects (unpublished observation). Hence their
  inability to maximally dilate their airways
  appears rooted in a defect in the airway wall
  and/or airway smooth muscle
• In SCI the elevation in Rmin is most likely
  caused by an inability to generate sufficient
  transpulmonary pressure and/or a defect at the
  level of the airway smooth muscle. The latter
  might result from the reduction in stretch due to
  reductions in tidal volumes, and/or failure to
  sigh on a regular basis. Even when they do sigh
  there is less stretch due to their lower IC.
  Both could lead to an increase in ASM stiffness
  and contractility and to atelectasis which is
  unresolvable with a DI. Also inhibiting vagal
  tone does not entirely resolve the airway
  wall/ASM stiffness.

Figure 2 Rrs to Rmin traces for each subject
group

• Healthy subjects had the lowest Rrs and Rmin.
  When a challenge is administered to a healthy
  subject their Rrs could be increased to that of a
  baseline asthmatic, however there is only a minor
  increase in Rmin.
• Asthmatics have a significantly higher Rmin when
  compared to healthy subjects at baseline and post
  challenge.
• Subjects with SCI have also have an elevated Rrs
  and Rmin which are both statistically
  significantly larger than healthy subject.

Protocol

• Data from 8 healthy pre and post bronchial
  challenge, and 10 asthmatics pre and post
  bronchial challenge were acquired from a previous
  study (2)
• New data from 27 SCI (8 Cervical, 13 Thoracic,
  and 6 Lumbar) subjects has been acquired
• 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
• FRC Data was measured via helium dilution

plt0.05 when compared to healthy at baseline
plt0.05 based on paired T test
Summary
N10
N5
N8
N8
N13
N26

Figure 5 Rmin as a function of Rrs,IC, and FEV1
predicted


Subject 1

• Subject groups in which enhanced airway
  hyperreactivity is reported also show a depressed
  ability to maximally dilate their airways.
• The primary mechanisms controlling maximal
  dilation is likely a function of maximal elastic
  recoil pressure and airway smooth muscle
  stiffness.
• Current and past data indicate that in asthma
  abnormalities in ASM is the primary contributor
  to hyperreactivity.
• In SCI it remains unclear if ASM is abnormal or
  if increased Rrs is a result of low lung volumes
  (low FRC and TLC). Future studies should measure
  elastic recoil pressure during the same maneuvers
  and also test the reactivity of each subject
  group explicitly.

• The SCI subjects and asthmatic subjects have a
  similar correlation between Rmin as a function of
  Rrs and this correlation is markedly different
  from that of healthy subjects, who seem to have a
  plateau in Rmin achievable.
• The Rmin does not correlate with IC or FEV1.
• The FEV1 vs. Rmin data can differentiate cleanly
  between healthy and asthmatic subjects.

DI
Post Challenge
Thoracic SCI
Cervical SCI
Lumbar SCI
Post Chal
Baseline
Baseline
All SCI
Subject2
References
DI
Rmin

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 96506-515
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
   95511-518
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 175333-341

Figure 3 Rmin for each subject group

• Healthy subjects have the smallest Rmin value,
  which becomes slightly increased by bronchial
  challenge.
• Asthmatic Rmin are elevated at baseline and more
  so after challenge.
• Subjects with SCI all have values that are
  similar to that of baseline asthmatics. If the
  subject with a Lumbar injury in figure 2, that
  has a very distinct resistance value from all
  other SCI subjects is omitted (see figure 2),
  then there is evidence of a trend for Rmin to be
  dependent on injury level. Specifically subjects
  with cervical SCI have the highest Rmin.

Figure 1 Raw data for 2 SCI subjects with
thoracic injuries
FRC
FRC
FRC
TLC
TLC
TLC

• Both subject 1 and 2 have a similar elevated
  Rmin (1.75 and 1.6 respectively), however subject
  1s inspiratory capacity is 4 times larger than
  subject 2s.

Figure 6 FRC pred. And TLC pred for subjects
with SCI

• The decreased FRC values could be partly
  responsible for the increased Rrs at baseline,
  possibly even independent of airway tone. The
  decrease in FRC could be caused by atlectasis, or
  by increases in lung stiffness.

Supported by NIH HLB 62269, the DVA Cooperative
Studies Program and NIH R01 HD42141