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  • Edward Ingenito. Brigham and Womens Hosp Boston. Check RV stats. Check explanation for abscess. Primer solution removes epithelial cells from target area. Bovine serum is heat inactivated and given to neutralise primer. Hydrogel – glycosaminoglycans + synthetic polyamine promotes fibroblast attachment + collagen synthesis = fibrosis. Check ? Whole lobe fibroses. ?avoids collateral ventilation
  • These are his chest x rays before and after the procedure. There is progressive collapse of the upper part of the lung with re-expansion of the lower lobe and pulling of the diaphragm.
  • N=19
  • N=19 Mean endurance Tlim at 80% maximum workload increased from 227 (129) seconds to 315 (195) seconds (p=0.03). Patients who developed atelectasis are represented by open triangles.
  • Durch LTx

Transcript

  • 1.  
  • 2. Endobronchial blockers for Lung Volume Reduction Michael I Polkey Consultant Physician & Reader in Respiratory Medicine Royal Brompton Hospital, London SW3 [email_address]
  • 3. LVRS-THE EVIDENCE Randomised controlled trials n=262 Criner AJRCCM 1999 160 2018 Geddes NEJM 2000 343 239 Pompeo Ann Thor Surg 2000 70 948 Lofdahl ATS 2000 A487 Goodnight-White ATS 2000 A486 -15 -10 -5 0 5 10 15 20 25 30 FEV 1 6MD deaths % LVRS Control
  • 4. Fishman et al NEJM 2003; 348; 21:2059-73
  • 5. If LVRS works, can we make it simpler, safer, cheaper?
  • 6. Non Surgical Approaches
    • Collapse non-functional lung
      • Endobronchial ‘glue’
      • Endobronchial Valves
    • Increase non-bronchial drainage from the lung
      • Broncus
  • 7. Endoscopic ‘Glue’
    • 12 sheep – papain induced emphysema
    • 4 each – LVRS, sham bronchoscopy, BLVR
    • Used fibrin-based glue (BistechSeal)
    • TLC, RV fall similar
    • 55% success-collapse
    • 15% sterile abscess
    • 6 sheep – papain
    • Enzyme primer solution
    • Washed out – fetal bovine serum
    • Modified hydrogel scaffold
    • 3/52: TLC -16%, RV -55%. No abscess
    • 91% success – fibrosis/contraction
    • Human trials
    Ingenito. AJRCCM 2001;164:295-301 Ingenito. AJRCCM 2003;167:771-778
  • 8. Chest 2007;131:1108-1113 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
  • 9. Intra Bronchial Valve (IBV) Spiration
  • 10. Zephyr TM Transcopic EBV TM Valve
    • One-way Valve
    • Valve Protector
    • Self-expanding Retainer
    • Silicone
    • Seal
    Airflow Airflow Emphasys Endobronchial Valves Classic Type EBV TM Valve
  • 11. Toma et al Lancet 2003;361(9361): 931-33
  • 12. Before 1 day 2 days 8 days
  • 13. DH after endobronchial valves Hopkinson et al Am J Resp Crit Care Med 2005; 171:453-460
  • 14. Pulmonary function   Baseline Four weeks FEV 1 (% 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)* TL CO 3.3 (1.1) 3.7 (1.2)* K CO 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
  • 15. Change in endurance time after BLVR p=0.03
  • 16. Lung Volume Reduction improves mechanics
  • 17. VENT Study
    • Shows ?
  • 18. Conclusion
    • Lung Volume Reduction Surgery
      • Effective if patients carefully chosen
      • Significant mortality and failure rate
    • Emerging therapies
      • RCT’s lacking; till now
  • 19. 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 Thanks to the team
  • 20. Treatment Lung transplantation and lung volume reduction Heinrike Wilkens, Gerhard W. Sybrecht Universitätsklinikum des Saarlandes Innere Medizin V D – 66421 Homburg/Saar ERS Research Seminar September 28-29th 2007, Como, Italy
  • 21. 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
  • 22. Therapeutic options for D.U.
    • LVR ?
      • homogeneus Emphysema
      • DLCO 16 %
      • 2003
        • no ideal candidate for surgical LVR
    • LTX
  • 23. ADULT LUNG TRANSPLANTATION: Indications for Single Lung Transplants and double lung transplants (Transplants: January 1995 - June 2006, Total 17.616) ISHLT 2007 J Heart Lung Transplant 2007;26:782 COPD SLTx COPD DLTx n=4305 n=2225
  • 24.
    • 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
    D.U.56 J.
  • 25.
    • 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.
  • 26. 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
  • 27. Endexpiratory and endinspiratory total and compartmental chest wall volumes Vcw (l) Vrc pul (l) Vrc abd (l) Vab (l)
  • 28. Volumes of the abdominal rib cage (before LTx) COPD Cystic fibrosis Pulmonary fibrosis
  • 29. Minute Ventilation and workload
  • 30. Relationship between tidal volume and breathing frequency at rest and during exercise
    • COPD: pattern very similar to normal, with Vt and BF increasing.
    • PF and CF different pattern, increase in minute ventilation by increasing breathing frequency (rapid and shallow breathing).
  • 31. Relationship between inspiratory flow and duty cycle at rest and during exercise
  • 32. after lung transplantation
  • 33. Increased minute ventilation and workload after LTx COPD Cystic fibrosis Pulmonary fibrosis
  • 34. Relationship between tidal volume and breathing frequency at rest and during exercise before and after LTx
  • 35. Relationship between duty cycle and inspiratory flow before and after lung transplantation
  • 36. 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
  • 37.
    • 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
    D.U.56 J.
    • 2006 weight loss, malaise, jaundice
      • abdominal sonography and computed tomography
      • pancreatic carcinoma Stage V
  • 38.
    • retrospective
    • LVRS 1994-1998
    • LTx 1994-2000
    2007
  • 39. Lung transplatation in COPD
    • can dramatically improve QOL
    • but there is no good evidence for improved survival rate
    • Stavem, K., O. Bjortuft, et al. (2006). &quot;Lung transplantation in patients with chronic obstructive pulmonary disease in a national cohort is without obvious survival benefit.&quot; Heart Lung Transplant 25(1): 75-84.
    • Hosenpud et al. Lancet 1998; 351: 24–27
    • LTx may not always be the best treatment choice
  • 40.
    • Geddes et al.
    • N Engl J Med 2000 343:4 239-45
    Effect of lung-volume-reduction surgery in patients with severe emphysema Lung volume reduction surgery versus conservative treatment in 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 Fishman et al NEJM 2003; 348; 21:2059-73
  • 41. PATIENTS AT HIGH RISK OF DEATH AFTER LUNG-VOLUME–REDUCTION SURGERY National Emphysema Treatment Trial Research Group N Engl J Med, Vol. 345, No. 15 October 11, 2001 FEV1 < 20% and DLCO < 20% or Homogeneous Emphysema randomization N=70 conservative N=70 LVRS
  • 42. How to treat homogeneus Emphysema?
  • 43. Emphasys™ Spiration™ Pulmonix™ Watanabe Spigots™ Exhale™ Devices for bronchoscopic lung volume reduction
  • 44. 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
  • 45.  
  • 46. Video of an Exhale Stent
  • 47. I.I.
  • 48. 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
  • 49. Airway Bypass Results * *p<0.05 * * * *
  • 50. Breathing patterns after Airway Bypass Hyperinflator - Euvolumic Euvolumic- Hyperinflator
  • 51. 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)
  • 52. Key Inclusion Criteria
    • > 35 years
    • HRCT Homogenous emphysema
      • Determine by Core Lab
    • Pulmonary Function Tests/Plethysmography
      • FEV 1 /FVC < 70%
      • FEV 1 < 50% predicted or < 1L
      • RV/TLC > 0.69 (new 0.65)
      • DL co > 15% predicted
    • PaO 2 > 45mmHg room air
    • Supervised pulmonary rehabilitation therapy
      • 16-20 sessions over 6-10 weeks
  • 53. Europe EASE Sites - All Univ Med Center Otto Wagner Saarland Clinic Royal Brompton OUE Sites : The Alfred Hospital, Melbourne Santa Casa Hospital, Porto Alegre, Brazil 14 centers in US-States Mater Misericordiae Fundación Jiménez Díaz Papworth Asklepios Fachkliniken Policlinico Milano Thoraxklinik Nottingham City Hosp.
  • 54. Current / Investigational Therapies Homogeneous Heterogeneous Investigational Surgical Medical X Airway bypass (Endoscopic) X Biologic LVR (Endoscopic) X Endobronchial valves (Endoscopic) X X Lung transplantation X Lung volume reduction surgery (LVRS) X X Supplemental oxygen X X Pulmonary rehabilitation X X Steroids X X Long-acting bronchodilators Emphysema Distribution
  • 55. Number of Publications (Pubmed) COPD/Exercise 0 10 20 30 40 50 60 70 80 90 100 1950-1960 1961-1970 1971-1980 1981-1990 1991-2000 2001 02 03 04 05 06 07
  • 56. 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.
  • 57. ADULT LUNG TRANSPLANTATION: Indications (1/1995-6/2006) ISHLT 2007 J Heart Lung Transplant 2007;26: 782-795 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 Bronchiolitis 111 (1.3%) 85 (0.9%) 196 (1.1%) Obliterative Bronchiolitis (Not Re-Transplant) 46 (0.6%) 103 (1.1%) 149 (0.8%) Re-Transplant: Not Obliterative Bronchiolitis 76 (0.9%) 70 (0.8%) 146 (0.8%) 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%)
  • 58. VO2 max and workload in COPD 0 5 10 15 20 25 after before VO 2 max ml/kg/min 0 20 40 60 80 100 120 140 before after max Watt 4-10 7-33 0-30 55-159 .
  • 59. 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
    • max results from ventilation, cardiac output and oxygen 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),
    VO 2 .
  • 60. Volumes of the abdominal rib cage before and after LTx COPD Cystic fibrosis Pulmonary fibrosis