Controversies in COPD by ert554898

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									Endobronchial blockers for Lung
      Volume Reduction




Michael I Polkey
Consultant Physician & Reader in Respiratory Medicine
Royal Brompton Hospital, London SW3

m.polkey@rbh.nthames.nhs.uk
               LVRS-THE EVIDENCE
                               LVRS   Control

          30
          25
          20
          15
          10
       %
           5
           0
          -5    FEV1            6MD             deaths
         -10
         -15



                                         Criner AJRCCM 1999 160 2018
                                         Geddes NEJM 2000 343 239
Randomised controlled trials n=262       Pompeo Ann Thor Surg 2000 70 948
                                         Lofdahl ATS 2000 A487
                                         Goodnight-White ATS 2000 A486
Fishman et al NEJM 2003; 348; 21:2059-73
If LVRS works, can we make it
    simpler, safer, cheaper?
    Non Surgical Approaches
• Collapse non-functional lung
  • Endobronchial ‘glue’
  • Endobronchial Valves
• Increase non-bronchial drainage from
  the lung
  • Broncus
                   Endoscopic ‘Glue’
    • 12 sheep – papain             • 6 sheep – papain
      induced emphysema             • Enzyme primer solution
    • 4 each – LVRS, sham           • Washed out – fetal
                                      bovine serum
      bronchoscopy, BLVR            • Modified hydrogel
    • Used fibrin-based glue          scaffold
      (BistechSeal)                 • 3/52: TLC -16%, RV -
    • TLC, RV fall similar            55%. No abscess
                                    • 91% success –
    • 55% success-collapse            fibrosis/contraction
    • 15% sterile abscess           • Human trials

Ingenito. AJRCCM 2001;164:295-301   Ingenito. AJRCCM 2003;167:771-778
CT scan image from a group 2 patient showing localized infiltrates 1 week after
BLVR at the treatment site, changing into linear density by 1 month after BLVR




                                                           Chest 2007;131:1108-1113
Intra Bronchial Valve (IBV)
         Spiration
  Emphasys Endobronchial Valves

               One-way Valve

               Valve Protector

               Self-expanding
                 Retainer

                  Silicone
                    Seal



Classic Type                     ZephyrTM Transcopic
   Airflow                                   Airflow
EBVTM Valve                         EBVTM Valve
Toma et al Lancet 2003;361(9361): 931-33
Before   1 day




2 days   8 days
DH after endobronchial valves
                             3



                            2.5
 Inspiratory Capacity (L)




                             2



                            1.5



                             1



                            0.5



                             0
                                  Baseline   4 weeks



Hopkinson et al Am J Resp Crit Care Med 2005; 171:453-460
                   Pulmonary function
                   Baseline              Four weeks

FEV1 (% Pred)      28.4 (11.9)           31.5 (13.2) *

TLC (L)            9.1 (1.5)             8.8 (1.5)*

RV (L)             5.8 (1.7)             5.23 (1.7)

FRC (L)            7.09 (1.5)            6.61 (1.7)*
TLCO               3.3 (1.1)             3.7 (1.2)*

KCO                0.68 (0.2)            0.73 (0.2)*

                                     Mean (SD)         * p<0.05
          Hopkinson et al Am J Respir Crit Care Med 2005:171:453-460
              800
                    Change in endurance time after BLVR
              700



              600



              500
Tlim (secs)




              400



              300



              200



              100                                p=0.03


                0

                        Baseline           4 weeks
Lung Volume Reduction improves mechanics

                           2

                         1.5

                           1

    Delta VT/PoesSwing   0.5
        (mls/cmH2O)
                           0
   -40            -20           0                20   40
                         -0.5

                          -1

                         -1.5
                                    Delta EELV
                          -2            (L)
     VENT Study

•Shows ?
               Conclusion
• Lung Volume Reduction Surgery
  • Effective if patients carefully chosen
  • Significant mortality and failure rate
• Emerging therapies
  • RCT’s lacking; till now
                                           Thanks to the
                                           team




Our Research has been Funded by
      British Lung Foundation, British Heart Foundation,
      Wellcome Trust, Cystic Fibrosis Trust
      European Union, Ministry of Defence
      European Respiratory Society
     ERS Research Seminar September 28-29th 2007,
                     Como, Italy

                  Treatment
Lung transplantation and lung volume reduction




              Heinrike Wilkens, Gerhard W. Sybrecht
               Universitätsklinikum des Saarlandes
                         Innere Medizin V
                     D – 66421 Homburg/Saar
D.U.50 y.
     • Respiratory insufficiency (CRF)
       (PO2 7,9 Kpa, PCO2 6,5 Kpa pH 7,38 with
       transtracheal oxygen therapy 2 l/min)

     • FEV1 0,7 l ( 20 % pred.)
     • TLC               (112 % pred.)
     • RV/TLC                65 % pred.
     • DLCO                  16 % pred.
     • BMI 19, weight loss 5 kg in 1 year
     • 6-min walk 150 m
         – BODE-Index 9
     • homogeneus emphysema
         – Dyspnea at rest
         – decreasing exercise capacity
            despite ongoing pulmonary
            rehabilitation
Therapeutic options for D.U.

                  LVR ?
                      homogeneus
                       Emphysema
                      DLCO 16 %
                    2003
                           no ideal candidate
                            for surgical LVR


                       LTX
                          ADULT LUNG TRANSPLANTATION: Indications for
      Single Lung Transplants and                                 double lung transplants
                              (Transplants: January 1995 - June 2006, Total 17.616)




Alpha-1         COPD         CF           IPF           PPH            Re-TX
          3%                                                                                 7%
                                                                                      12%
                                   29%
                                                                                                  17%


      COPD                                   1%
      SLTx                                                 29%                                    2%
                                                 2%

                                                                                       n=2225
             n=4305
57%                                                                                   COPD
                                             8%                                                   9%
                                                                                      DLTx

                                                                                       24%


           ISHLT                                    2007
          J Heart Lung Transplant 2007;26:782
                               D.U.56 J.

     • 1998 first referral for LTx
          – Pulmonary rehabilitation
          – SCOOP

     •   2003 functional deterioration
     •
     •   FEV1 0,65 l (24 %)
          – 2004 waiting list LTx


2004 right sided single lung transplantation
 FEV1   2,1 l (58% pred.)
  PaO2 10,9 Kpa
  PaCO2 5,1 Kpa
  6-min-walk 510 m
•   44 lung transplant recipients (44.8
    + 11.6 years
     –   single LTx 14 recipients (10
         Emphysema)
     –   bilateral LTx 30 recipients (14
         Emphysema)


•   improvements on FEV1, 6MWT, and
    SGRQ
     –   lower FEV1 values were observed in
         patients following a single graft (p <
         0.01).
     –   6MWT and the SGRQ scores were
         not significantly different between
         recipients of single and double LTx.
      breathing pattern and chest wall volume variations
    during rest and exercise in lung transplant candidates
•   ventilatory parameters and chest wall
    configuration at end inspiration and
    end expiration in 39 LTx-candidates
•
       9 pts with cystic fibrosis
        •    age 32+10 y, FEV1 22+9

       9 pts with pulmonary fibrosis
        •    age 54+12 y, FEV1 38+11

       21 pts with COPD
        •    age 54+5y, FEV1 21+5

OEP with exercise testing
       2 minutes quiet breathing (qb)
        2 min unloaded pedelling
       increase in exercise every 2 minutes
       4 minutes of recovery
       Endexpiratory and endinspiratory total and
       compartmental chest wall volumes
                                           CTR                  COPD                  CF                   F
                               2.5

                               2.0
              Vcw (liters)


                               1.5

Vcw (l)                        1.0

                               0.5

                               0.0

                               -0.5
                               1.1

                               0.9
              Vrc,p (liters)




                               0.7

Vrc pul (l)                    0.5

                               0.3

                               0.1

                               -0.1

                               0.7


                               0.5
              Vrc,a (liters)




Vrc abd (l)                    0.3


                               0.1


                               -0.1
                               1.2

                               0.8
              Vab (liters)




Vab (l)                        0.4

                               0.0

                               -0.4

                               -0.8
                                      QB   0 watt   Wmax   QB    0 watt   Wmax   QB   0 watt   Wmax   QB   0 watt   Wmax
                      Volumes of the abdominal rib cage (before LTx)
                                        COPD pre
                                        COPD trapianto                                                                                                                                            Pulmonary fibrosis
                                                                                                                                                                                                  Fibrosi polmonare pre trapianto

               3.0
                                                                                                                                                                             3.0
                                                                                                                                                                                         EE pre
                                                                                                                                                                                         EI pre
               2.5                      EE pre                                                                                                                               2.5         EE controllo
                                                                                                                                                                                         EI controllo
                                        EI pre
               2.0                      EE controllo
                                                                                                                                                                             2.0
                                        EI controllo
VCW (Liters)




                                                                                                                                                             VCW (Liters)
               1.5


                      •
                                                                                                                                                                             1.5

               1.0                                                                                                                                                           1.0


               0.5                                                                                                                                                           0.5


               0.0


               -0.5
                      •                                                                                                                                                      0.0


                                                                                                                                                                            -0.5


               -1.0                                                                                                                                                         -1.0
                          0   20   40       60         80   100   120        140              160   180                                                                              0      20          40   60      80   100   120   140   160   180

                                                 carico (W)                                                                                                                                                       carico (W)
                                                                                                                  Cystic fibrosis
                                                                                                                  Fibrosi cistica pre post trapianto

                                                                                       3.0


                                                                                       2.5              EE pre
                                                                                                        EI post
                                                                                       2.0              EE ctr
                                                                                                        EI ctr
                                                                        VCW (Liters)




                                                                                       1.5


                                                                                       1.0


                                                                                       0.5


                                                                                       0.0


                                                                                       -0.5


                                                                                       -1.0
                                                                                              -20   0        20       40    60    80    100   120      140             160     180

                                                                                                                             carico (W)
Minute Ventilation and workload
                     80


                     70


                     60
  vent min (L/min)



                     50


                     40


                     30


                     20                                              COPD
                                                                     Fibrosi polmonare
                     10                                              Fibrosi cistica
                                                                     Controllo

                     0
                          -20    0   20   40   60   80   100   120     140     160       180

                                               carico (W)

                                Ventilation VT  freq
Relationship between tidal volume and breathing
      frequency at rest and during exercise

                     70

                                                                                    COPD
                                                                                    Cystic fibrosis
                     60                                                             Pulmonary fibrosis
                                                                                    Healthy
                                                                                                           •   COPD: pattern very
                                                                                                               similar to normal,
Frequency (br/min)




                     50                                               80
                                                                 70
                                                                                                               with Vt and BF
                                                           60                                                  increasing.
                     40
                                                      50
                                                 40
                     30                     30
                                                                                                           •   PF and CF different
                                                                                                               pattern, increase in
                                     20
                                                                                                               minute ventilation
                     20                                                                                        by increasing
                                10
                                                                                                               breathing frequency
                     10                                                                                        (rapid and shallow
                          0.5             1.0              1.5                2.0    2.5             3.0       breathing).
                                                                VT (liters)
                          Relationship between inspiratory flow and duty cycle at
                                         rest and during exercise
                     70                                                                                                        53
                                                                                                                                                                                                                           80
                                                                                    COPD                                                   COPD
                                                                                    Fibrosi cistica                                        Fibrosi cistica
                     60                                                             Fibrosi polmonare                                      Fibrosi polmonare
                                                                                                                               48          Controllo
                                                                                    Controllo
Frequency (br/min)




                     50                                                                                                                                                                                               70
                                                                      80




                                                                                                              Duty Cycle (%)
                     40
                          •                                60
                                                                 70                                                            43


                                                      50                                                                                                                                                        60



                          •
                                                 40                                                                            38
                     30                     30                                                                                                                                                             50

                                     20
                                                                                                                               33                                                               40
                     20
                                10                                                                                                                                              30

                                                                                                                                          10                   20
                     10                                                                                                        28
                          0.5             1.0              1.5                2.0    2.5                3.0                         0.3        0.6    0.9           1.2        1.5        1.8        2.1        2.4             2.7
                                                                VT (liters)                                                                                               VT/Ti (L/sec)




                                                                                                    1                          VT TI
                          •          VentilationVT  freq VT                                                                       insp flow duty cycle
                                                                                                TTOT                           TI TTOT
     after
     lung
transplantation
                            Increased minute ventilation and
                                  workload after LTx
                                   COPD pre post trapianto
                                                                                                                                                                                    fibrosi polmonare pre post trapianto
                   80                  COPD                                                                                                                 80                     Pulmonary fibrosis
                   70
                                                                                                                                                            70

                   60
                                                                                                                                                            60                               **
                                 ***
Ve' (Liters/min)




                                                                                                                                        Ve' (Liters/min)
                   50
                                                                                                                                                            50




                   •
                   40
                                                                                                                                                            40

                   30
                                                                                                                                                            30

                   20                                                                                                                                       20
                                                                                          pre                                                                                                                                pre



                   •
                                                                                          post                                                                                                                               post
                   10                                                                                                                                       10                                                               CTR
                                                                                          CTR

                    0                                                                                                                                        0
                        0   20    40    60      80   100                      120       140       160    180                                                           0           20   40    60      80   100   120   140   160    180
                                             carico (W)                                                                                                                                            carico (W)
                                                                                                                     fibrosi cistica pre post trapianto
                                                                                                               Cystic fibrosis
                                                                                80


                                                                                70
                                                                                                               **
                                                                                60
                                                           Ve' (Liters/min)




                                                                                50


                                                                                40


                                                                                30


                                                                                20                                                                                     pre
                                                                                                                                                                       post
                                                                                                                                                                       CTR
                                                                                10


                                                                                    0
                                                                                              0     20     40       60      80   100   120                 140   160         180

                                                                                                                         carico (W)
                                     Relationship between tidal volume and breathing
                                           frequency at rest and during exercise
                                                before     and after LTx
                     70
                                                                                                                                       70
                                                                                        COPD
                                                                                        Fibrosi cistica                                                                                          COPD
                     60                                                                                                                                                                          Fibrosi cistica
                                                                                        Fibrosi polmonare                              60                                                        Fibrosi polmonare
                                                                                        Controllo

                           •
                                                                                                                                                                                                 Controllo
Frequency (br/min)




                     50




                                                                                                                  Frequency (br/min)
                                                                      80                                                               50                                          80
                                                                 70                                                                                                           70

                     40
                           •                          50
                                                           60
                                                                                                                                       40
                                                                                                                                                                   50
                                                                                                                                                                        60


                                                 40                                                                                                           40
                     30                     30                                                                                         30                30

                                     20                                                                                                            20

                     20                                                                                                                20
                                10                                                                                                            10


                     10                                                                                                                10
                          0.5             1.0              1.5                2.0        2.5                3.0                             0.5         1.0             1.5                2.0        2.5            3.0
                                                                VT (liters)                                                                                                  VT (liters)




                                                                                    VentilationVT  freq
                                             Relationship between duty cycle and inspiratory flow
                                                     before and after lung transplantation
                 53                                                                                                                        53
                                                                                                                   80                                                                                                       80
                                 COPD                                                                                                                                     COPD
                        Zu r Anzei ge wi rd d er Qu ickTi me™                                                                                                Zu r Anzei ge wi rd d er Qu ickTi me™
                                Fibrosi „TIFF
                           Dekomp re ssorcistica (LZW)“                                                                                                         Dekomp reFibrosi cistica
                                                                                                                                                                           ssor „TIFF (LZW)“
                                      be polmonare
                                Fibrosi nöti gt.                                                                                                                           be nöti gt.
                                                                                                                                                                          Fibrosi polmonare
                 48              Controllo                                                                                                 48                             Controllo



                            •                                                                                 70




                                                                                                                          Duty Cycle (%)
Duty Cycle (%)




                 43                                                                                                                        43                                                                                    70




                 38         •                                                                           60
                                                                                                                                           38                                                                                60

                                                                                                   50

                                                                                       40                                                                                                                             50
                 33                                                                                                                        33
                                                                       30                                                                                                                                  40
                                                                                                                                                                                             30
                                10                   20                                                                                                                20
                                                                                                                                                      10
                 28                                                                                                                        28
                      0.3            0.6      0.9          1.2        1.5        1.8         2.1        2.4             2.7                     0.3    0.6    0.9           1.2           1.5        1.8        2.1   2.4             2.7
                                                                 VT/Ti (L/sec)                                                                                                    VT/Ti (L/sec)



                                                                                             1           VT TI
                                           Ventilation VT                                                     insp flow duty cycle
                                                                                            TTOT         TI TTOT
                 Lung transplation

• leads to normalisation of breathing pattern

• leads to improved exercise tolerance
  – 40-60 % of healthy subjects
     • peripheral factors impairing adequate oxygen supply to
       exercising muscles (e.g. microcirculatory or cellular level)?
             (Ross et al. 1993, Biring et. al. J. Appl. Physiol. 84(6): 1967–1975, 1998)




• studies about effect of exercise training on
  exercise performance still need to be done
                           D.U.56 J.
• 1998 first referral for LTx
    – Pulmonary rehabilitation
    – SCOOP

• 4/2003 functional deterioration
•
• FEV1 0,65 l (24 %)
    – 8/2003 waiting list LTx
• 2004 right sided single lung
  transplantation



• 2006 weight loss, malaise, jaundice
    –abdominal sonography and computed tomography


        pancreatic carcinoma Stage V
• retrospective
•   LVRS 1994-1998
•   LTx 1994-2000




                     2007
     Lung transplatation in COPD

                          • can dramatically improve
                            QOL

                          • but there is no good
• LTx may not always        evidence for improved
                            survival rate
  be the best treatment
  choice

                          Stavem, K., O. Bjortuft, et al. (2006). "Lung
                              transplantation in patients with chronic
                              obstructive pulmonary disease in a national
                              cohort is without obvious survival benefit."
                              Heart Lung Transplant 25(1): 75-84.


                          Hosenpud et al. Lancet 1998; 351: 24–27
Effect of lung-volume-reduction        Lung volume reduction surgery
 surgery in patients with severe      versus conservative treatment in
           emphysema                         severe emphysema




                                    H. Wilkens, G.W. Sybrecht et al.
                                    Eur Respir J 2000; 16: 1043±1049

                                   LVRS is effective in selected patients,
                                   NETT-Study: subgroup analysis
                                   survival benefit for patients with
                                   heterogeneus emphysema
                                                 and low exercise capacity
D. Geddes et al.
N Engl J Med 2000 343:4 239-45     Fishman et al NEJM 2003; 348; 21:2059-73
    PATIENTS AT HIGH RISK OF DEATH
AFTER LUNG-VOLUME–REDUCTION SURGERY
   National Emphysema Treatment Trial Research Group



                                                                        FEV1 < 20%
                                                                        and
                                                                        DLCO < 20%
                                                                        or

                                                                        Homogeneous
                                                                        Emphysema
                                                                        randomization
                                                                        N=70
                                                                        conservative
                                                                        N=70 LVRS




                      N Engl J Med, Vol. 345, No. 15 October 11, 2001
      How to treat

homogeneus Emphysema?
 Devices for bronchoscopic lung volume reduction




Emphasys™            Spiration™          Pulmonix™




 Watanabe Spigots™
                                  Exhale™
            Airway Bypass Procedure
• Homogeneous emphysema
• Hyperinflation
• Collateral ventilation
      General anesthesia or deep sedation

      Place up to 3 stents per lung
           Patient’s CT scan used to identify potential stent sites

      Procedure takes 1- 2 hours
Zur Anzeige wird der QuickTime™
 Dekompressor „MPEG-4 Video“
             benötigt.
Video of an Exhale Stent




   Zur Anzeige wird der QuickTime™
    Dekompressor „YUV4 20 co dec“
                benötigt.
I.I.
                Key Clinical Endpoints
               Feasibility Study - Change at 6 Months over Baseline
          for patients with initial RV/TLC ratio above the median of 0.67*



Study Population (n=18)        Mean Change             % Change              p-value

Residual Volume (RV)                 -870 mL             -14.1%               0.022

Total Lung Capacity (TLC)            -460 mL             -5.6%                0.12

Forced Vital Capacity (FVC)                              17.8%                0.065

Dyspnea Index (mMRC)                 -0.5                                     0.035



 *data accepted for publication in JTCVS
                                      Airway Bypass
                                         Results


                                      Change in RV from baseline
                  1.000
                  0.500                                             *
                                               *
                  0.000
Mean Change (L)




                  -0.500                                                -0.446         -0.448
                                                   -0.760
                  -1.000
                                                                                                 *p<0.05
                  -1.500                                                -0.973          -0.930

                  -2.000                           -1.206

                  -2.500
                                                                    *
                  -3.000
                                                                                       *
                  -3.500                       *
                           Baseline        Month 1               Month 3            Month 6

                                       All patients         Severe hyperinflation
                                                                                                                                                  EE
                                                                                    Tushe                                                         EI

                     2.0



                     1.5
                                                                                                                                                                  Breathing patterns
                     1.0
                                                                                                                                                                  after Airway Bypass
Vcw (liters)




                     0.5



                     0.0



                     -0.5                                                                                                                                       Hyperinflator - Euvolumic
                     -1.0
                             qb 0w 10w20w30w40w    qb 0w 10w20w30w40w50w    qb 0w 10w20w30w40w50w   qb 0w 10w20w30w40w50w   qb 0w 10w20w30w40w50w

                                                                                      Edeur

                       1.5




                       1.0
      Vcw (liters)




                       0.5




                       0.0




                      -0.5




                      -1.0
                              qb 0w 10w        qb 0w 10w 20w    qb 0w 10w 20w 30w      qb 0w 10w 20w 30w     qb 0w 10w 20w 30w        qb 0w 10w 20w 30w


                                                                                       Illre

                       2.0




                       1.5
      Vcw (liters)




                       1.0




                       0.5




                       0.0




                      -0.5                                                                                                                                      Euvolumic- Hyperinflator
                                  qb      0w            qb     0w     10w    20w               qb   0w     10w   20w             qb      0w     10w       20w
 EASE Trial - Exhale Airway Stents for
             Emphysema


 Controlled, double-blind, randomized, multi-
  center

 Sham control arm

 2:1 randomization (treatment:sham)

 225+ patients (Bayesian/adaptive statistics)
             Key Inclusion Criteria
 > 35 years
 HRCT Homogenous emphysema
   – Determine by Core Lab
 Pulmonary Function Tests/Plethysmography
   – FEV1/FVC < 70%
   – FEV1 < 50% predicted or < 1L
   – RV/TLC > 0.69    (new 0.65)
   – DLco > 15% predicted
 PaO2 > 45mmHg room air
 Supervised pulmonary rehabilitation therapy
   – 16-20 sessions over 6-10 weeks
Europe EASE Sites - All


Mater
Misericordiae
                          Nottingham
                          City Hosp.
                                        Univ Med Center
                Papworth
                    Royal
                    Brompton
                                              Thoraxklinik

                           Saarland Clinic
                                             Asklepios       Otto Wagner
                                             Fachkliniken



                                              Policlinico
                                                Milano



          Fundación                                                        OUE Sites:
          Jiménez Díaz
                                                                            The Alfred Hospital, Melbourne
                                                                            Santa Casa Hospital, Porto Alegre, Brazil
                                                                            14 centers in US-States
                           Current / Investigational Therapies
                                                                      Emphysema Distribution
                                                                   Heterogeneous   Homogeneous

                            Long-acting bronchodilators                 X               X
                            Steroids                                    X               X
Medical




                            Pulmonary rehabilitation                    X               X
                            Supplemental oxygen                         X               X
                            Lung volume reduction surgery (LVRS)        X
Surgical Investigational




                            Lung transplantation                        X               X
                            Endobronchial valves (Endoscopic)           X
                            Biologic LVR (Endoscopic)                   X
                            Airway bypass (Endoscopic)                                  X
  Number of Publications (Pubmed)
100                      COPD/Exercise
90

80

70

60

50

40

30

20

10

 0
      1950- 1961- 1971- 1981- 1991-   2001 02   03   04   05   06   07
      1960 1970 1980 1990 2000
                   Publications
• Pre-clinical
  – Feasibility and safety of airway bypass stent placement and
    influence of topical mitomycin C on stent patency. Choong CK,
    Haddad FJ, Gee EY, Cooper JD. J Thorac Cardiovasc Surg. 2005
    Mar;129(3):632-8.
  – Prolongation of patency of airway bypass stents with use of
    drug-eluting stents. Choong CK, Phan L, Massetti P, Haddad FJ,
    Martinez C, Roschak E, Cooper JD. J Thorac Cardiovasc Surg.
    2006 Jan;131(1):60-4.

• Clinical
  – Feasibility and safety of the airway bypass procedure for
    patients with emphysema. Rendina EA, De Giacomo T, Venuta F,
    Coloni GF, Meyers BF, Patterson GA, Cooper JD. J Thorac
    Cardiovasc Surg. 2003 Jun;125(6):1294-9.
  – DES Feasibility Study: Accepted to J Thorac Cardiovasc Surg.
          ADULT LUNG TRANSPLANTATION: Indications                     (1/1995-6/2006)

           DIAGNOSIS              SLT (N = 8,316)   BLT (N = 9,300)       TOTAL (N = 17,616)
COPD/Emphysema                     4,305 (52%)       2,225 (24%)              6,530 (37%)
Idiopathic Pulmonary Fibrosis      2,193 (26%)       1,217 (13%)              3,410 (19%)
Cystic Fibrosis                     167 (2.0%)       2,722 (29%)              2,889 (16%)
Alpha-1                             626 (7.5%)        795 (8.5%)             1,421 (8.1%)
Primary Pulmonary Hypertension      65 (0.8%)         575 (6.2%)              640 (3.6%)
Sarcoidosis                         178 (2.1%)        260 (2.8%)              438 (2.5%)
Bronchiectasis                      30 (0.4%)         473 (5.1%)              503 (2.9%)
LAM                                 59 (0.7%)         116 (1.2%)              175 (1.0%)
Congenital Heart Disease            16 (0.2%)         132 (1.4%)              148 (0.8%)
Re-Transplant: Obliterative         111 (1.3%)        85 (0.9%)               196 (1.1%)
Bronchiolitis
Obliterative Bronchiolitis          46 (0.6%)         103 (1.1%)              149 (0.8%)
(Not Re-Transplant)
Re-Transplant: Not Obliterative     76 (0.9%)         70 (0.8%)               146 (0.8%)
Bronchiolitis
Connective Tissue Disease           51 (0.6%)         65 (0.7%)               116 (0.7%)
Interstitial Pneumonitis            24 (0.3%)         13 (0.1%)                37 (0.2%)
Cancer                               7 (0.1%)         12 (0.1%)                19 (0.1%)
Other                               362 (4.4%)        437 (4.7%)              799 (4.5%)


   ISHLT                                 2007
 J Heart Lung Transplant 2007;26: 782-795
         VO2 max and workload in COPD


.
VO2 max                    max
ml/kg/min                  Watt
    25                     140
                           120
    20
                           100
    15                      80
    10                      60
                            40
    5
          4-10     7-33     20
                                  0-30     55-159
    0                       0
          before   after          before   after
                        after Lung Transplantation
• improved lung function and normal cardiopulmonary function at rest
• But:
    – Exercise capacity and VO2 max markedly decreased (40-60 % pred.)
    – decreased anaerobic threshold

•
     .
     VO   max results from ventilation, cardiac output and oxygen
          2
    extraction of sceletal muscles
    – almost normal ventilation
    – normal cardiac function
          • Deconditioning ?
          • peripheral factors impairing adequate oxygen supply to
            exercising muscles (e.g. microcirculatory or cellular level)?
               (Ross et al. 1993, Biring et. al. J. Appl. Physiol. 84(6): 1967–1975, 1998)
              – Cyclosporin A leads to mitochondrial myopathy and diminished endurance
                (Mercier 1995),
                                   Volumes of the abdominal rib cage
                                         before and after LTx
                               COPD                        EE pre                                                                                     Pulmonary fibrosis
                                                                                                                                                    Fibrosi polmonare pre post trapianto
                               COPD pre post trapianto     EI post
                                                           EI pre
                                                           EE post
               2.0                                                                                                                            EI pre
                                                                                                                                              EE post
                                                                                                                                 2.0
                                                                                                                                              EI pre
                                                                                                                                              EE post
               1.5
                                                                                                                                 1.5
                                                                                                                                                                                           ***




                                                                                                                  VCW (Liters)
               1.0
VCW (Liters)




               0.5    •                                                                                                          1.0



                                                                                                                                 0.5
               0.0                                       ***
               -0.5
                      •                                                                                                          0.0



               -1.0       **                                                                                                     -0.5
                          0         20            40           60
                                                                                     Cystic fibrosis post trapianto
                                                                                         Fibrosi cistica pre                                   0            20         40          60            80

                                     carico (W)                                                                                                                  carico (W)
                                                                              1.5



                                                                              1.0



                                                                              0.5
                                                               VCW (Liters)




                                                                              0.0



                                                                              -0.5

                                                                                      EE pre
                                                                                      EE post
                                                                              -1.0
                                                                                      EI pre                                            ***
                                                                                      EI post

                                                                              -1.5
                                                                                       0        20           40                    60              80

                                                                                                     carico (W)

								
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