Optimizing the Donor Lung with EVLP

Transcription

1 Optimizing the Donor Lung with EVLP Marcelo Cypel MD MSc FRCSC Canada Research Chair in Lung Transplantation Surgical Director ECLS Lung Program UHN Associate Professor of Surgery Division of Thoracic Surgery Department of Surgery University of Toronto

2 Disclosure Founding Partner: Perfusix Canada Inc. Perfusix USA Inc. (Lung Bioengineering /UT) XOR Labs Toronto Inc. XVIVO Perfusion Research support and clinical trial United Therapeutics Consultant Xenios/Fresenius Research support and investor in XOR Gilead Sciences Research Support

3 Low Utilization Rates of Donor Lungs BDD=17% DCD=2% 2015: 20% NDD and 2% DCD

4 Munshi L, Keshavjee S, Cypel M. Lancet Resp. Medicine Feb 2013

5 Christie, J. et al, J Heart Lung Transplant November ; 29(11): Clinical Problem PGD 3

6 Gold Standard Preservation ( ) Cold Static Preservation

7 Cold Preservation At 4 º C cellular metabolism is reduced to about 5% of normal Protective injurious processes (dying) slowed Problem: Injured organs cannot be actively improved/repaired 7

8 Normothermic Ex vivo Lung Perfusion Time to accurately assess, diagnose (improve utilization) Option to treat, recover, repair (targeted) Opportunity to reassess confirm results of treatment

9 EVLP Physiological Paradigms 1) Perfusate flow: low vs high 2) Pump flow: continuous vs pulsatile 3) Perfusate composition: acellular vs cellular(blood) 4) Perfusate temperature: cold, 25ᵒC or 37ᵒC 5) Left Atrial Pressure: 0 vs 5 mmhg 6) Ventilation Strategy: low Vt vs high Vt, PEEP? 7) Supply of CO 2 to perfusate: required or not

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

11 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):

12 12 NEJM, April 14 th 2011, vol. 364, no. 15, pp

13 Donor for 1 st Clinical EVLP (October 2008) 20 yo male MVA trauma 21 units RBC transfusion PaO 2 range mmhg CXR pulmonary edema Bronchoscopy Bloody secretions

14 Donor CXR

15 EVLP Xrays 1h EVLP P/F 250mmHg 3h EVLP P/F 460mmHg 15

16 Recipient CXR on ICU Arrival

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

18 EVLP for high risk donor lungs is safe EVLPs vs. 133 matched controls Survival probability (%) EVLP No Yes Time (Years) Number at risk EVLP: No EVLP: Yes Yeung, J. JHLT

19 Indications for EVLP 1) Unusable Donor : EVLP treatment 2) Questionable Donor 3) Standard cdcd EVLP testing 4) Extended cdcd 5) Logistics (safe prolongation of preservation period) 19

20 Unusable Lung 1) Massive Edema 2) Pneumonia 3) Aspiration 4) Massive Pulmonary Emboli 5) Chronic Virus Infection (i.e Hep C) 6) Long Warm Ischemia in Controlled and Uncontrolled DCD 20

21 Treatment Strategies Perfusion Cell Therapy Gene Therapy Drugs Immuno-cloaking Biological Inhaled Gases 21

22 22 Pulmonary Edema

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

24 24 9 years alive

25 Adjunct Therapies to Improve Edema Proper perfusion/ventilation strategies (Linacre V et al; Importance of Left Atrium Strategy in EVLP; JHLT 2016) Use of drugs to stimulate AFC Matthay M A et al. J Appl Physiol 2002;93: Sakuma T, Crit Care Med Mar;34(3):

26 26 Pneumonia

27 Infection Large proportion of rejected human lungs EVLP is ideal Super high doses of antibiotics can be administered without systemic effects Prolonged half-life. Prolonged perfusion (>12h) might be required 27

28 Significant decrease of bacteria during EVLP Nakajima et al. Am J Transplant 2016 Apr;16(4):

29 Treatment of Infection is Associated with Improved Lung Function Nakajima et al. Am J Transplant 2016 Apr;16(4):

30 30 Aspiration

31 Aspiration Very common cause for donor lung decline More prevalent in DCDs after WLST Nakajima D, ISHLT

32 Superior post-transplant function with lung lavage followed by surfactant replacement PaO 2 /FiO 2 (mmhg) * * * * 1h 2h 3h 4h Control Lavage Surfactant Lavage + Surfactant Nakajima, JHLT, 2017 May;36 (5):

33 33 Pulmonary Emboli

34 Case Report 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):

35 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) Machuca et al. Am J Respir Crit Care Med Oct 1;188(7):

36 Significant improvement of Pulmonary Hemodynamics Alteplase diagnosis treatment Response monitoring

37 Pathology: Ex vivo lung biopsy, Quick Section No evidence of chronic vascular abnormalities Machuca et al. Am J Respir Crit Care Med Oct 1;188(7):

38 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

39 Donor Lungs with Infectious Diseases: Hep C actual donors/year in North America Young donors, good lungs Lungs are not offered for transplant due to ~ 100% chance of transmission for RNA+ donors 39

40 Case Report Donor 60 years old, male Stroke intracranial hemorrhage Last ABG PaO2 179 mmhg Hepatitis C: RNA+ Recipient Male, 44 years old Pulmonary Fibrosis Transplant in 2013 Admitted to ICU: Severe hypoxemia P/F 48 mmhg

41 Harvoni (12 weeks) 41 EVLP Effect Khan B et al. Am J Transplant doi: /ajt

42 42 Light-based therapy (UVC) during EVLP

43 UVC is effective to eradicate HCV infectivity and replication Treated perfusate Cell culture infection Results qpcr from RealTime PCR Inactivation of HCV IU /m L Tim e (m in) UVC Control Infectivity log TCID50/mL Loss of infectivity Tim e (m in) Control (n=4) UVC (n=4) Loss of infectivity

44 44 Inflammation

45

46 Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs resulted in improved lung function Change from Baseline (mmhg) PaO 2 /FiO * (dynes.sec.cm -5 ) PVR * EVLP/AdIL-10 EVLP

47 P = IL-8 in perfusate (pg/ml) P = * IV 150M Control Mordant / Keshavjee et al. J Heart Lung Transplant Oct;35(10): h 6h 12h (Repeated ANOVA & Bonferroni post-tests)

48 EVLP in 2018 Great tool to test quality of donor lungs: NDD and DCD Allow simple treatment strategies (i.e. drugs) to improve most common causes of donor lung injury Significantly prolong preservation times 48

49 EVLP in Future.. Platform for major advances in organ transplantation including: Cell and Genetic modification: Gene Therapy, MSC, T regs Immuno-cloaking Organ modification in Xenotransplantation Platform for patient own organ repair Bioreactor for Decel/Recel 49

50