Lung Transplantation:Where we are and Where we are going… Shaf Keshavjee MD MSc FRCSC FACS Director, Toronto Lung Transpla...
Disclosure    • Vitrolife – Research support and clinical trial    • Astellas Canada – Research Grant    • CIHR/ Wyeth (Pf...
OVERVIEW                     Lung Transplantation   Overview of Lung Transplantation:       Activity, indications outcom...
Indications for Lung Transplantation          Adult (1983-Apr 2012)               Adults         ILD / IPF                ...
Indications for Transplantation     Pediatric (1983-Apr 2012)         N=48 (3.7 %)
6                       No of Tx / yr                                              100                                    ...
7                              No of Tx / yr                        20                             40                     ...
NUMBER OF LUNG TRANSPLANTS REPORTED                            BY YEAR AND PROCEDURE TYPE                                 ...
LUNG TRANSPLANTS:                    Recipient and Donor Age by Year of Transplant                   100%                 ...
AVERAGE CENTER VOLUME                                                     Lung Transplants                    60          ...
ADULT LUNG TRANSPLANTS                                     (1/1997-6/2009)                                                ...
ADULT LUNG TRANSPLANTATION               Kaplan-Meier Survival by Era                                     (Transplants: Ja...
ADULT LUNG TRANSPLANTATION               Kaplan-Meier Survival by Age Group (Transplants: January 1990 – June 2009)       ...
ADULT LUNG TRANSPLANTATION               Kaplan-Meier Survival By Diagnosis                              (Transplants: Jan...
Waiting List, Transplants and Donors                                           (All Organs-Ontario)                       ...
Death on Waiting List, Total LTx/yr &                     Listed/yr                  2004-Jan/2012 (YTD)     Numbers16
Solutions to Deaths on the Wait List     •Keep the patient alive longer and in      better condition  Bridge to      Tran...
Selection of ECLS Support Mode /ConfigurationCypel/Keshavjee ECMO Red Book, 4th edition, 2011.
NovalungR
NovalungPumpless A-V Mode: Femoral Artery to Femoral      Vein (extra-corporeal ventilation)
V-V ECLSCardioHelp Device
Novalung iLAactivve
Dual Lumen Canula (AvalonR)• One canula inserted through right  internal jugular vein• Drainage from IVC and SVC   oxygen...
Bridge to Lung Transplant for PAH Patients          Simple Atrial Septostomy is UnsatisfactoryPA                          ...
Novalung PA to LA             Bridge to Lung Transplant for PAH Patients                   “The Oxygenating Septostomy”   ...
June 2008
Dec 2008
Number of days on PA-LA Novalung                           200Days on PA-LA Novalung                           180        ...
ECLS decreases wait list mortality in                        iPAH patients: Toronto experience                            ...
ECLS Toronto Experience                                 2000 – 2012 (10Apr2012)                                          n...
IMPROVING SUPPLY:Focus on Organ Recovery and Repair Rather than   Simply Focusing on Slowing Down Death…                  ...
Normothermic Ex Vivo Lung Perfusion                  (EVLP)• Time to accurately assess - diagnose• Option to treat/repair/...
TORONTO EX VIVO LUNG                     PERFUSION (EVLP) SYSTEMPerfusion : 40% COVentilation: 7cc/kg, 7BPM, PEEP 5, FiO2 ...
DEVELOPMENT OF A STABLE AND RELIABLE             EX VIVO LUNG PERFUSION TECHNIQUECypel/Keshavjee. Technique for Prolonged ...
Normothermic Ex vivo Lung Perfusion in Clinical Transplantation – HELP Trial
HELP II TRIALCLINICAL TRANSPLANTATION OF EX VIVO          PERFUSED LUNGS         N=52 transplants to date     Toronto Gene...
Bronchoscopy
LUNG X-Ray
Ex vivo treatment opportunities Donor lung injuries• 1- Pulmonary Edema• 2- Brain death associated inflammation• 3- Infect...
Diagnose Specific Injuries:                     The expression ratio of IL-6/IL-10 in the donor lung predicts             ...
Monitoring theResponse to                      Pre-EVLP sample 1-22 Post-EVLP sample 1-22Ex VivoTreatmentZiplex Inflammato...
Functional Repair of Human Donor Lungs             by Ex Vivo IL-10 Gene Therapy     Delivery of IL-10 by EVLP Ad Gene The...
April 14th 2011, vol. 364, no. 15, pp. 1431-1440.44
Resolution of pulmonary edema during       EVLP                                    1h EVLPDonor P/F 230                   ...
Donor, EVLP and Recipient P/F (n=35)                       P/F       600       500       400mmHg       300       200      ...
Overall Survival                   100                                                                   Control (n=116)  ...
EVLP Activity /Year                     1983-Apr 2012(YTD) 120                    EVLP pre Tx 100                    LuTx-...
Operative (30 day) Mortality by year                      1983-April 2012 (YTD)                    120                    ...
The Future of Transplantation is here…             The “Organ Repair Center”Lung                                          ...
Case Report (April 2011)    • 52 y old male in US    • Viral Pneumonia    • 7 days ventilator – extubated    • Day 14 – re...
April 2011
Love R et al. Am J Transplantation 2012. In press
Ex vivo Lung Perfusion:                The Toronto Experience•   Clinically feasible•   Increases the utilization of donor...
The Toronto Lung Transplant Team
Webinar Conducted by     In association          with
Lung Transplantation - Where we are and Where we are going
Lung Transplantation - Where we are and Where we are going
Lung Transplantation - Where we are and Where we are going
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Lung Transplantation - Where we are and Where we are going

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Overview of Lung Transplantation
Changing the practice of clinical lung transplantation
Ex vivo lung perfusion, personalized medicine for the organ, engineering "super organs"

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Lung Transplantation - Where we are and Where we are going

  1. 1. Lung Transplantation:Where we are and Where we are going… Shaf Keshavjee MD MSc FRCSC FACS Director, Toronto Lung Transplant Program Surgeon-in-Chief, University Health Network James Wallace McCutcheon Chair in Surgery Professor, Division of Thoracic Surgery and Institute of Biomaterials and Biomedical Engineering University of Toronto
  2. 2. Disclosure • Vitrolife – Research support and clinical trial • Astellas Canada – Research Grant • CIHR/ Wyeth (Pfizer) – Chair in Transplantation Research • Axela, Xceed Molecular – Research Grant • Will discuss off label use of devices2
  3. 3. OVERVIEW Lung Transplantation Overview of Lung Transplantation:  Activity, indications outcomes Changing the practice of clinical lung transplantation  Expansion of indications  Bridge to transplant New Horizons  Ex vivo lung perfusion, personalized medicine for the organ, engineering “super organs”
  4. 4. Indications for Lung Transplantation Adult (1983-Apr 2012) Adults ILD / IPF BAC PAH CF Eisenmengers COPD /Emphysema ReTx Other N=1245 (96.3 %)
  5. 5. Indications for Transplantation Pediatric (1983-Apr 2012) N=48 (3.7 %)
  6. 6. 6 No of Tx / yr 100 120 0 20 40 60 80 83 84 85 BLT SLT HLT 86 87 88 89 90 91 92 93 94 95 96 97 Year 98 99 00 01 02 03 04 1983-Apr 2012 (YTD) 05 06 07 08 09 10 Number of Transplants / Year 11 12
  7. 7. 7 No of Tx / yr 20 40 60 80 100 120 0 83 84 85 86 Adults 87 88 89 90 91 Peds 92 93 94 95 96 97 Year 98 99N Peds =48 00 01 02 (1983-Apr 2012)-YTD 03 Adult vs. Pediatric 04 05 Total Transplants / Year 06 07 08 09 10 11 12
  8. 8. NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE www.ishlt.org 3500 3272 2972 Bilateral/Double Lung 2917 3000 2791 Single LungNumber of transplants 2567 2500 2216 n = 38,119 1971 2008 2000 1783 1699 1509 1548 1559 1411 1389 1500 1291 1160 972 1000 758 449 500 204 38 89 5 7 0 19 5 19 6 19 7 19 8 19 9 19 0 19 1 19 2 19 3 19 4 19 5 19 6 19 7 19 8 20 9 20 0 20 1 20 2 20 3 20 4 20 5 20 6 20 7 20 8 09 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 19 ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  9. 9. LUNG TRANSPLANTS: Recipient and Donor Age by Year of Transplant 100% 50 Median donor age (years) 80% 40% of transplants 60% 30 40% 20 20% 10 0% 0 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 Year of Transplant 0-11 12-17 18-34 35-49 50-59 60+ Median Donor Age ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  10. 10. AVERAGE CENTER VOLUME Lung Transplants 60 24 50 20 Percentage of transplantsNumber of centers 40 16 30 12 54 20 39 8 10 28 23 4 16 7 7 0 0 1-4 5-9 10-19 20-29 30-39 40-49 50+ Average number of lung transplants per year Number of centers Percentage of transplants ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  11. 11. ADULT LUNG TRANSPLANTS (1/1997-6/2009) Risk Factors for 1 Year Mortality Center Volume 2Relative Risk of 1 Year Mortality 1.5 1 0.5 p < 0.0001 0 5 10 15 20 25 30 35 40 45 50 Center Volume (cases per year) ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  12. 12. ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival by Era (Transplants: January 1988 – June 2009) 100 Survival comparisons by era 1988-1994 (N=4,548) 1988-94 vs. 1995-99: p = 0.4858 1995-1999 (N=6,795) 1988-94 vs. 2000-6/09: p <0.0001 2000-6/2009 (N=20,728) 1995-99 vs. 2000-6/09: p <0.0001 80Survival (%) 60 N at risk =552 40 N at risk = 841 20 1988-1994: 1/2-life = 4.7 Years; Conditional 1/2-life = 7.9 Years N at risk = 702 1995-1999: 1/2-life = 4.8 Years; Conditional 1/2-life = 7.5 Years 2000-6/2009: 1/2-life = 5.9 Years; Conditional 1/2-life = 8.0 Years 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  13. 13. ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival by Age Group (Transplants: January 1990 – June 2009) 100 HALF-LIFE 18-34: 6.4 Years; 35-49: 6.7 Years; 50-59: 5.3 Years; 60-65: 4.4 Years; >65: 3.5 Years 80 Survival comparisons All p-values significant at p < 0.0001 except 18-34 vs. 35-49: p =0.1708Survival (%) 60 40 18-34 (N = 5,523) 35-49 (N = 7,980) 20 50-59 (N = 11,389) 60-65 (N = 5,685) >65 (N = 1,217) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  14. 14. ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival By Diagnosis (Transplants: January 1990 – June 2009) 100 Alpha-1 (N=2,349) CF (N=4,828) COPD (N=10,741) IPF (N=6,478) IPAH (N=1,189) Sarcoidosis (N=756) 80 HALF-LIFE Alpha-1: 6.3 Years; CF: 7.4 Years; COPD: 5.3 Years; IPF: 4.5 Years; IPAH: 4.9 Years; Sarcoidosis: 5.3 YearsSurvival (%) 60 40 Survival comparisons All comparisons with Alpha-1 and CF are 20 statistically significant at < 0.01 COPD vs. IPF: p < 0.0001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years ISHLT 2011 J Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132
  15. 15. Waiting List, Transplants and Donors (All Organs-Ontario) (Source: TGLN 1991-2011) 2500 1892 1913 1857 2000 1745 1766 1720 1650 1676 16831631 1557 1461 1498 1408 1500Number of Patients 1271 1116 1171 926 953 916 940 837 827 928 875 852 1000 799 765 667 700 641 686 693 727 617 536 529 498 528 456 499 507 500 133 145 139 151 150 200 175 218 200 220 161 151 150 133 166 128 137 143 153 148 172 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Waiting List(all) Transplants(all) Ont. Donors© 15
  16. 16. Death on Waiting List, Total LTx/yr & Listed/yr 2004-Jan/2012 (YTD) Numbers16
  17. 17. Solutions to Deaths on the Wait List •Keep the patient alive longer and in better condition  Bridge to Transplant •Increase the supply of donor organs17
  18. 18. Selection of ECLS Support Mode /ConfigurationCypel/Keshavjee ECMO Red Book, 4th edition, 2011.
  19. 19. NovalungR
  20. 20. NovalungPumpless A-V Mode: Femoral Artery to Femoral Vein (extra-corporeal ventilation)
  21. 21. V-V ECLSCardioHelp Device
  22. 22. Novalung iLAactivve
  23. 23. Dual Lumen Canula (AvalonR)• One canula inserted through right internal jugular vein• Drainage from IVC and SVC  oxygenated blood returned to right atrium• Allows mobilisation of extubated patients Garcia/Griffith et al J Thorac Cardiovasc Surg 2010;139:e137-9
  24. 24. Bridge to Lung Transplant for PAH Patients Simple Atrial Septostomy is UnsatisfactoryPA LA RV failure 20 to Pulmonary Vascular Resistance Atrial Septostomy:  provides pressure decompression  problem: R-L shunt, hypoxia
  25. 25. Novalung PA to LA Bridge to Lung Transplant for PAH Patients “The Oxygenating Septostomy” PA LA 1. Pumpless 2. Effectively: an oxygenating shunt  provides pressure decompression AND gas exchangeStrueber / Keshavjee et al. Am J Transplant 2009; 9: 853-7.
  26. 26. June 2008
  27. 27. Dec 2008
  28. 28. Number of days on PA-LA Novalung 200Days on PA-LA Novalung 180 160 140 120 100 80 69* 60 40 30* 21 20 9 14 *Pediatric patients 7 6
  29. 29. ECLS decreases wait list mortality in iPAH patients: Toronto experience Wait list mortality: 22%  0% 25 Number of patients 20 Patients liste 15 Patients tran 10 Died on wait p=0.03 5de Perrot 0 al J Heart Lung Transplant 2011 et 1998-2005 2006-2010
  30. 30. ECLS Toronto Experience 2000 – 2012 (10Apr2012) n = 100 20 18 Bridge to recovery (non-Tx) 16 Bridge to recovery post-transplant 14Nr of ECLS Bridge to lung transplant 12 10 8 6 4 2 0 2000 2002 2004 2006 2008 2010 2012(ytd) Year
  31. 31. IMPROVING SUPPLY:Focus on Organ Recovery and Repair Rather than Simply Focusing on Slowing Down Death… Good Better
  32. 32. Normothermic Ex Vivo Lung Perfusion (EVLP)• Time to accurately assess - diagnose• Option to treat/repair/recover• Opportunity to reassess - confirm results of treatment
  33. 33. TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEMPerfusion : 40% COVentilation: 7cc/kg, 7BPM, PEEP 5, FiO2 = 21% J Heart Lung Transplant 2008; 27(12):1319-25.
  34. 34. DEVELOPMENT OF A STABLE AND RELIABLE EX VIVO LUNG PERFUSION TECHNIQUECypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo LungPerfusion. J Heart Lung Transplant 2008;27(12):1319-25.
  35. 35. Normothermic Ex vivo Lung Perfusion in Clinical Transplantation – HELP Trial
  36. 36. HELP II TRIALCLINICAL TRANSPLANTATION OF EX VIVO PERFUSED LUNGS N=52 transplants to date Toronto General Hospital OR
  37. 37. Bronchoscopy
  38. 38. LUNG X-Ray
  39. 39. Ex vivo treatment opportunities Donor lung injuries• 1- Pulmonary Edema• 2- Brain death associated inflammation• 3- Infection, Pneumonia• 4- Aspiration• 5- Pulmonary emboli• 6- Ischemia-reperfusion injury• 7- Immunologic preparation
  40. 40. Diagnose Specific Injuries: The expression ratio of IL-6/IL-10 in the donor lung predicts recipient outcome 1.0 0.8 Low risk group Survival 0.6 Intermediate risk group High risk group 0.4 0.2 The Wilcoxon test P value: 0.0004 0.0 0 365 730 1095 1460 1825 Survival DaysKaneda H / Keshavjee S et al. Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans. Am J Transplant 2006 Mar; 6 (3):544-51.
  41. 41. Monitoring theResponse to Pre-EVLP sample 1-22 Post-EVLP sample 1-22Ex VivoTreatmentZiplex InflammatoryTip ChipR (Axela) Pre EVLP Post EVLP
  42. 42. Functional Repair of Human Donor Lungs by Ex Vivo IL-10 Gene Therapy Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs resulted in improved lung function PaO2/FiO2 PVR Change from Baseline 300 * 600 (dynes.sec.cm-5) 400 200 (mmHg) 200 100 0 -200 0 -400 -100 -600 * EVLP/AdIL-10 EVLPM Cypel, M Liu, M Rubacha, J C Yeung, S Hirayama, M Anraku, M Sato, J Medin, BLDavidson, M de Perrot, TK Waddell, A S Slutsky, S Keshavjee. Sci Trans. Med 1:4ra9; 2009.
  43. 43. April 14th 2011, vol. 364, no. 15, pp. 1431-1440.44
  44. 44. Resolution of pulmonary edema during EVLP 1h EVLPDonor P/F 230 3h EVLPRecipient P/F 420
  45. 45. Donor, EVLP and Recipient P/F (n=35) P/F 600 500 400mmHg 300 200 100 0 1h 2h 3h 4h or U IC on D EVLP
  46. 46. Overall Survival 100 Control (n=116) 80 EVLP (n=23)Percent survival 60 p=0.77 40 median f/u 635 days 20 0 0 200 400 600 800 1000 Days after transplantation
  47. 47. EVLP Activity /Year 1983-Apr 2012(YTD) 120 EVLP pre Tx 100 LuTx-no EVLP 80No of Tx / yr 60 40 20 0 83 94 84 85 86 87 88 89 90 91 92 93 95 96 97 98 99 11 00 01 02 03 04 05 06 07 08 09 10 12 Year 53/65 EVLP was successfully Transplanted 48
  48. 48. Operative (30 day) Mortality by year 1983-April 2012 (YTD) 120 100 102 102 Death <=30-d 100 87 85 Number of transplants 84 Number of TX 80 68 64 59 54 60 50 42 40 36 38 32303133 40 2727 2524 14 15 13 20 6 6 1 2 1 3 3 1 2 7 2 1 2 3 1 4 4 2 39 7 4 25 5 4 6 1 0 1 8 321 0 Year49
  49. 49. The Future of Transplantation is here… The “Organ Repair Center”Lung HeartLiver Kidney
  50. 50. Case Report (April 2011) • 52 y old male in US • Viral Pneumonia • 7 days ventilator – extubated • Day 14 – re-intubated • Day 22 – VV – ECMO • Day29 – deterioration – bleeding complications • Day 30 urgently listed for LTx • Day 32 – Donor is identified in another state. • Massive pulmonary edema and P/F 230mmHgLove R et al. Am J Transplantation 2012. In press
  51. 51. April 2011
  52. 52. Love R et al. Am J Transplantation 2012. In press
  53. 53. Ex vivo Lung Perfusion: The Toronto Experience• Clinically feasible• Increases the utilization of donor lungs (20% of our current program activity)• Equivalent outcomes  trend to improved post transplant lung function• Demonstrated the concept of the “organ repair center”• New era of transplantation: • “Personalized medicine for the organ”: • More accurate assessment • Treatment  specific injuries • Lung transplantation with more predictable outcome
  54. 54. The Toronto Lung Transplant Team
  55. 55. Webinar Conducted by In association with

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