Marcelo Cypel MD MSc

Transcription

1 Ex vivo Organ Repair Marcelo Cypel MD MSc Canada Research Chair in Lung Transplantation Surgical Director ECLS Program UHN Assistant Professor of Surgery Division of Thoracic Surgery University Health Network University of Toronto

2 DISCLOSURE XVIVO Perfusion Research support and clinical trial Founding Partner: Perfusix Canada Inc. Perfusix USA Inc. XOR Labs Toronto Inc.

3 Current Standard Practice in Organ Selection and Management Donor Management Decline 85% (Questionable organs are declined at procurement) Decision Organ Procurement Cold Static Preservation Slows down death Unable to assess function Transplantation (15%) PGD rate = 30%

4 Low Utilization Rates BDD=17% DCD=2%

5 Munshi L, Keshavjee S, Cypel M. The Lancet RM Feb 2013

6 Clinical Problem - PGD

7 First Successful Lung Transplantation in the World Toronto General Hospital1983 G Pearson, J Cooper, A Patterson, T Todd

8 Reduction of cell metabolism by 95%

9 Manipulate Storage Temperature According to Organ / Clinical Needs: Hypothermic - Normothermic Time to accurately assess, diagnose (improve utilization) Option to treat, recover, repair (targeted) Opportunity to reassess confirm results of treatment

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11 Lindbergh, Science, 1935

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13 TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEM Perfusion : 40% CO, LAP 5mmHg, PAP 10-12mmHg Ventilation: 7cc/kg, 7BPM, PEEP 5, FiO 2 = 21% J Heart Lung Transplant 2008; 27(12):

14 DEVELOPMENT OF A STABLE AND RELIABLE EX VIVO LUNG PERFUSION TECHNIQUE Cypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo Lung Perfusion. J Heart Lung Transplant 2008;27(12):

15 NORMOTHERMIC EX VIVO PERFUSION INTERRUPTS COLD ISCHEMIC INJURY (24h) Cypel/Keshavjee. Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant Oct;9(10): CSP EVLP

16 16 NEJM, April 14 th 2011, vol. 364, no. 15, pp

17 Video

18 NEJM, April 14 th 2011 Early outcomes were similar in the 2 groups

19 19 What is the impact of EVLP to our program?

20 Clinical Experience with EVLP at UHN 213 EVLPs Conversion Rate = 78% 166LTx 47 declined

21 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 '15 Number of LTx Number of Donors Ontario Donors vs. LTx/Year 1991-Oct 22, 2015(YTD) % LTx/Year Year Deceased Donors (ON) 2121

22 % of Transplants are from EVLP lungs 50 % Transplants

23 Outcomes with Clinical EVLP p=0.956 (Log-Rank) 23

24 Tikkanen / Singer, JHLT 2015 Freedom from CLAD (EVLP of high risk NDDs)

25 How does EVLP rescue more lungs?

26 1) Improvement in Lung Assessment

27 27 DCD

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29 Jan 2007 to Oct DCD lung transplants 30 no EVLP transplants 32 EVLP transplants 3 ECLS cases 4 ECLS cases 27 no EVLP transplants 28 EVLP transplants Figure 4

30 Donor, Recipient and Early Outcome variable No EVLP EVLP p Donor Age Donor +ve culture 17 (62%) 23 (82%) 0.13 Donor P/F ratio Diagnosis IPF/PH 12 (44%) 13 (46%) 1 Age BMI Bilateral 21 (77%) 21 (75%) 1 Time on MV 3 (1-13) 2 (1-3) 0.05 ICU Stay 6 (2-17) 3 (2-7) 0.07 Hospital Stay 23 (16-41) 18 (14-22) 0.04

31 Reeb J, Keshavjee S, Cypel M. Journal of Heart and Lung Transplantation Oct 2015

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33 33 2) Treatment Strategies

34 Ex vivo treatment opportunities - Donor lung injuries

35 Treatment Strategies Perfusion Gene Therapy Drugs Cell Therapy Immuno-cloaking Biological Inhaled Gases 35

36 Resolution of pulmonary edema during EVLP Donor P/F 230 1h EVLP Recipient P/F 420 3h EVLP

37 Case Report # 2 History ABG P/F Chest X-ray Transthoracic ECHO RVSP Bronchoscopy Intra-operative PAP Antegrade and Retrograde Flush Thromboembolic disease 266 mmhg No infiltrates 52 mmhg + RV dysfunction, consistent with massive PE Clear bilaterally 41/30 mmhg Macroscopic clots extracted bilaterally Concern: Thrombotic/embolic history, Elevated RVSP, RV dysfunction, Heart turned down, PAH acute or chronic? Machuca et al. Am J Respir Crit Care Med Oct 1;188(7):

38 EVLP Assessment confirms the in vivo findings On initiation of EVLP: abnormal PA pressures even with low flows Persistent hemodynamic impairment in the ex vivo organ Apply similar diagnosis / treatment as in vivo treatment of massive PE ALTEPLASE 20 mg (reduced clearance)

39 Significant improvement of Pulmonary Hemodynamics after treatment Alteplase diagnosis treatment Response monitoring

40 D-dimer and Evidence of Thrombolysis Knecht et al. PE + fibrinolysis Thromb Res 1992 Brenner et al. MI + fibrinolysis Circulation fold increase 11-fold increase Ex vivo treated lung with massive PE 11-fold increase

41 Pathology: Ex vivo lung biopsy, Quick Section pathologic Examination No evidence of chronic vascular abnormalities

42 Donor vs. Recipient post-reperfusion P/F 266 mmhg RVSP 50 mmhg Right Ventricular dysfunction Intra-operative PAP 41/30 mmhg P/F > 500 mmhg PAP 28/9 mmhg Extubation 12 hours

43 Ongoing EVLP treatment projects Antibiotics human and animal models Surfactant+lung lavage human and animal models CO+H2S inhaled gas Anti-cell death treatment Immuno-cloaking Stem Cell

44 HEP C (>400 donors in USA/Year) Donor 60 years old, male Stroke intracranial hemorrhage Last ABG PaO2 179 mmhg Hepatitis C Recipient Male, 44 years old Pulmonary Fibrosis Rapid deteriorating list

45 Perfusate viral load HCV viral load (IU/ml) Hours of EVLP

46 Tissue viral load HCV viral load (IU/ml) Hours of EVLP

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48 Clinical EVLP projects 2015 IL-10 Gene Therapy -Phase I clinical trial (n=12) Non-Perfused Organ Donors (n=10) 48

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50 The Future of Transplantation The Organ Repair Center Lung Heart Liver Kidney

51 Commercial Devices for Ex Vivo Lung Perfusion Van Raemdonck et al. Transplant Int 2014 Mar 15. doi: /tri.12317

52 The Organ Hub Perfusix-1 (PX1, Lung Bioengineering Inc.)

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