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
DISCLOSURE XVIVO Perfusion Research support and clinical trial Founding Partner: Perfusix Canada Inc. Perfusix USA Inc. XOR Labs Toronto Inc.
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%
Low Utilization Rates BDD=17% DCD=2% www.unos.org.2011
Munshi L, Keshavjee S, Cypel M. The Lancet RM Feb 2013
Clinical Problem - PGD
First Successful Lung Transplantation in the World Toronto General Hospital1983 G Pearson, J Cooper, A Patterson, T Todd
Reduction of cell metabolism by 95%
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
Lindbergh, Science, 1935
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):1319-25.
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):1319-25.
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. 2009 Oct;9(10):2262-9 CSP EVLP
16 NEJM, April 14 th 2011, vol. 364, no. 15, pp. 1431-1440.
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NEJM, April 14 th 2011 Early outcomes were similar in the 2 groups
19 What is the impact of EVLP to our program?
Clinical Experience with EVLP at UHN 213 EVLPs Conversion Rate = 78% 166LTx 47 declined
91 92 93 94 95 96 97 98 99 '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) 150 1000 28% 133 115116 800 100 100 102 102 104 87 86 84 600 50 27 27 25 24 32 30 31 33 38 50 42 59 54 64 68 400 200 0 0 LTx/Year Year Deceased Donors (ON) 2121
% of Transplants are from EVLP lungs 50 % Transplants 40 30 20 10 0 2008 2009 2010 2011 2012 2013 2014 2015 22
Outcomes with Clinical EVLP p=0.956 (Log-Rank) 23
Tikkanen / Singer, JHLT 2015 Freedom from CLAD (EVLP of high risk NDDs)
How does EVLP rescue more lungs?
1) Improvement in Lung Assessment
27 DCD
Jan 2007 to Oct 2013 62 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
Donor, Recipient and Early Outcome variable No EVLP EVLP p Donor Age 39 19 45 13 0.16 Donor +ve culture 17 (62%) 23 (82%) 0.13 Donor P/F ratio 429 66 380 103 0.04 Diagnosis IPF/PH 12 (44%) 13 (46%) 1 Age 50 16 52 13 0.73 BMI 23 4 23 3 0.99 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
Reeb J, Keshavjee S, Cypel M. Journal of Heart and Lung Transplantation Oct 2015
33 2) Treatment Strategies
Ex vivo treatment opportunities - Donor lung injuries
Treatment Strategies Perfusion Gene Therapy Drugs Cell Therapy Immuno-cloaking Biological Inhaled Gases 35
Resolution of pulmonary edema during EVLP Donor P/F 230 1h EVLP Recipient P/F 420 3h EVLP
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. 2013 Oct 1;188(7):878-80.
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)
Significant improvement of Pulmonary Hemodynamics after treatment Alteplase diagnosis treatment Response monitoring
D-dimer and Evidence of Thrombolysis Knecht et al. PE + fibrinolysis Thromb Res 1992 Brenner et al. MI + fibrinolysis Circulation 1998 18-fold increase 11-fold increase Ex vivo treated lung with massive PE 11-fold increase
Pathology: Ex vivo lung biopsy, Quick Section pathologic Examination No evidence of chronic vascular abnormalities
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
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
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
Perfusate viral load 30000 25000 HCV viral load (IU/ml) 20000 15000 10000 5000 0 0 1 2 3 4 5 6 7 Hours of EVLP
Tissue viral load 60000 50000 HCV viral load (IU/ml) 40000 30000 20000 10000 0 0 1 2 3 4 5 6 7 Hours of EVLP
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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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The Future of Transplantation The Organ Repair Center Lung Heart Liver Kidney
Commercial Devices for Ex Vivo Lung Perfusion Van Raemdonck et al. Transplant Int 2014 Mar 15. doi: 10.1111/tri.12317
The Organ Hub Perfusix-1 (PX1, Lung Bioengineering Inc.)
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