ECLS Bridge to Lung Transplantation Optimizing and Ambulating the Recipient

ECLS Bridge to Lung Transplantation Optimizing and Ambulating the Recipient Shaf Keshavjee MD MSc FRCSC FACS Surgeon-in-Chief, University Health Network James Wallace McCutcheon Chair in Surgery Director, Toronto Lung Transplant Program Professor, Division of Thoracic Surgery and Institute of Biomaterials and Biomedical Engineering, Vice Chair, Innovation, Department of Surgery University of Toronto

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

ECLS Bridge to Lung Transplant ECLS bridge to LTx is being increasingly applied UNOS database analysis J Thorac Dis. 2014 Aug;6(8):1070-9. 3

Selection of Large Published Series Center year # of pts ECLS duration** Successful bridge to LTx 1-year survival of transplanted pts Hannover 2012 26 9d 62% 80%* Lexington # 2013 31 14d NA 93% Pittsburgh 2013 31 34d 78% 74% Munich 2013 26 16d 50% 54% Zurich 2015 26 21d 86% 68% Columbia 2017 72 12d 56% 90% Vienna 2017 124 5d 89% 67% Toronto 2017 71 10d 89% 76% * 6-months survival # multicenter study ** med vs. mean 4

Toronto Experience To review our experience of ECLS in patients bridged to LTx lessons learned To identify factors related to optimal bridging 5 J Thoracic Cardiovasc Surg 2017

Indications for ECLS Bridging Indications: severe hypercapnic + hypoxemic failure or hemodynamic failure (PPH) Candidacy for ECLS bridging is discussed by a multidisciplinary team in advance at the time of listing Exclusion (relative?) criteria: age > 65 years severe deconditioning BMI > 30 significant comorbidities (coronary artery disease, etc.) prolonged mechanical ventilation uncontrolled sepsis and other multi-organ dysfunction (except isolated kidney failure or liver dysfunction associated with PH) 6

Bridging Strategy Hypercapnic failure Hypoxic failure RV failure PH RV+LV failure Novalung Hemolung Single-cannula VV ECMO dual-cannula VV ECMO VA ECMO PA/LA Novalung 7

COUNT (n) Toronto Experience: Total Lung Transplants by Type (BLT, SLT, HLT) 180 160 140 120 100 80 60 40 20 0 1983 2017 YEAR BLT SLT H/L 8

ECLS activities by Indication/Year 2000-06/2016 (YTD)* No. of ECLS/year 90 Cardiac / Other 80 ARDS (non-tx) BTR (Post) 70 BTT (pre) 60 50 40 30 20 10 0 Year 9

10 Percentage of Patients Bridged to LTx

Evolution in Practice VV VV VV VA

CF 23 yo female pco 2 122 mmhg ph 7.18 Continuous BIPAP pco 2 68 mmhg ph 7.42

29 yo male CLAD, Hypercapnia

91 days on VV ECMO prior to Re-LTx

Discharge - going home and ambulatory!

Ambulation 37% were able to do physical therapy during bridging full ambulatory standing/stepping dangle bed exercises immobile full ambulatory standing/stepping dangle bed exercises immobile 17

Bridging Devices and Success of Extubation: Is Tracheostomy Better Than Extubation? Mean time of ECLS bridging: 14 days (range 0-95) Hemolung Novalung Single cannula VV ECMO Two cannula VV ECMO VA ECMO PA/LA Novalung Multiple devices extubated tracheostomized intubated 18

32 yo female with Cystic Fibrosis

Past Medical History 32yo female Cystic Fibrosis Chronically infected with Pseudomonas Progressive drop in lung function over last year (FEV 1 1.4L) Frequent exacerbations IV antibiotics and steroid Considering lung transplant assessment but doing relatively well Exocrine pancreatic insufficient, CF related diabetes, DIOS Married, 3 yo daughter

Current Medical History Mar 2, 2016: Acute worsening of SOB, hypoxemia; FEV 1 dropped to 0.79L (23% Pred) Mar 9, 2016 Developed H1N1 pneumonia treated with Tamiflu Respiratory failure on BIPAP at outside hospital - developed worsening hypercapnia Apr 7, 2016 Intubated and transferred to TGH for urgent lung transplant assessment /bridge to LTx Apr 7, 2016 on admission

Assessment Summary Cardiac Echo: Normal sized LV with moderate LV dysfunction LVEF estimated at 30-40% Normal sized RV with mildly reduced function Enable to estimate RVSP ABG: ph 7.30, pco2 121, po2 216 (Apr 7 on ICU arrival) TLC (P): 5.5 (L) LAB DATA: Cr: 57 AST: 15 ALT: 18 ALP: 144 BILT: 3 INR: 1.05 ALB: 24 HbA1C: 0.091 Hb: 93 WBC: 24.0 Plt: 272 Listed on Apr 8, 2016 Status 2, Bilateral only

VV-ECMO for bridge to recovery/ bridge to lung transplant After admission to ICU Resp. condition deteriorated acutely ph 7.16, pco2 >140, po2 87 VV-ECMO was placed via 22 Fr RIJ and 25 Fr RF Tracheostomy After ECMO insertion Apr 7 Apr 8 Apr 15 ABG: ph 7.27 pco2 61 po2 67 Gradually Deteriorated, Needed increased ECLS Flow

Septic Shock and Persistent Bacteremia Developed septic shock Bacteremia with gram-negative Pseudomonas 3 vasopressors at maximum dose VASOPRESSIN, LEVOPHED, and ADRENALIN Despite VV ECMO (flow of 7 L/min), Significant hypoxemia (without pump recirculation) ABG: ph 7.14 pco2 52, po2 60 Refractory vasodilation - sepsis April 17, 2016

Remove the Septic Source: Bilateral Pneumonectomy Switch to Central VA-ECMO (22Fr aortic cannula, 34/46 two-stage IVC venous cannula Right-sided pneumonectomy first, then left pneumonectomy Insertion of Right lung PA-LA Novalung Outflow: Pulmonary arterial (34 Fr single-stage venous cannula) Inflow: right superior pulmonary vein (28 Fr Pacifico) April 17, 2016

Remove Septic Source: Bilateral Pneumonectomies

Bilateral Lung Transplant April 22, 2016 (5 days after pneumonectomy) On central VA-ECMO Left side implantation first ( CIT: 3h 15 min, WIT: 49 min) Removed the PA cannula from right PA (for the PA-LA Novalung) Removed the LA cannula from right superior pulmonary vein Right lung implantation ( CIT: 4h 45 min, WIT: 50 min) 6 U prbc and 2 U platelets Immediate Postop BLT

October 2016 J Thor Cardiovasc Surg 2016 Oct 19, 2016

Toronto Experience Retrospective analysis of our institutional ECLS bridging practice over the last 10 years January 2006 - September 2016 Total 1111 LTx 71 patients bridged to LTx 30

Outcomes Bridged patients Total n=71 Survived until LTx - yes 63 (89%) - no 8 (11%) PGD at 72hrs - PGD 0/1 9% - PGD 2 33% - PGD 3 57% Postoperative ECMO - no 36 (59%) - VV ECMO 16 (26%) - VA ECMO 9 (15%) Time to extubation (median, IQR) 18 (4;33) Total hospital days (median, IQR) 72 (50;122) 31

Outcomes Bridged patients Total n=71 Survived until LTx - yes 63 (89%) - no 8 (11%) PGD at 72hrs - PGD 0/1 9% - PGD 2 33% - PGD 3 57% Postoperative ECMO - no 36 (59%) - VV ECMO 16 (26%) - VA ECMO 9 (15%) Time to extubation (median, IQR) 18 (4;33) Total hospital days (median, IQR) 72 (50;122) 32

Outcomes Bridged patients Total n=71 Survival per intention-to-treat Survived until LTx - yes 63 (89%) - no 8 (11%) 70% bridged to LTx bridged to Re-LTx PGD at 72hrs - PGD 0/1 9% - PGD 2 33% - PGD 3 57% 53% 63% 51% Postoperative ECMO - no 36 (59%) - VV ECMO 16 (26%) - VA ECMO 9 (15%) Time to extubation (median, IQR) 18 (4;33) Total hospital days (median, IQR) 72 (50;122) 32% 32% p=0.045 33

Successful vs. Unsuccessful bridging No differences in: age, diagnosis, first/re-transplant, type of device, time on ECLS BUT!!! successful bridging unsuccessful bridging p-value n=63 n=8 Ventilation during bridging - no invasive MV 31 (49%) 1 (13%) 0.049 Ambulatory status - mobile/awake 25 (40%) 1 (13%) 0.133 34

Comparison of Bridged pts to LTx w/o Bridging Bridge to LTx LTx without Bridging n=71 n=1040 p-value Age (mean; range) 38 (18-62) 53 (18-77) < 0.001 Gender (m/f) 48%/52% 58%/42% 0.101 Height (mean±sd; cm) 165.3±10.3 168.2±9.8 0.021 Weight (mean±sd; kg) 62.3±15.5 67.5±15.4 0.006 BMI (mean±sd; kg/m 2 ) 22.4±5.2 23.8±4.6 0.014 Diagnosis (n; %) - COPD 3% 22% - Interstitial lung disease 37% 38% - Cystic Fibrosis 23% 16% - Pulmonary hypertension 18% 3% < 0.001 - CLAD 16% 2% - others 4% 19% Type of LTx - Double-LTx 92% 81% - Single-LTx 5% 18% < 0.001 - Heart-Lung Tx 3% 1% 35

Comparison of Bridged pts to LTx w/o Bridging Bridge to LTx LTx without Bridging n=71 n=1040 p-value Age (mean; range) 38 (18-62) 53 (18-77) < 0.001 Gender (m/f) 48%/52% 58%/42% 0.101 Height (mean±sd; cm) 165.3±10.3 168.2±9.8 0.021 Weight (mean±sd; kg) 62.3±15.5 67.5±15.4 0.006 BMI (mean±sd; kg/m 2 ) 22.4±5.2 23.8±4.6 0.014 Diagnosis (n; %) - COPD 3% 22% - Interstitial lung disease 37% 38% - Cystic Fibrosis 23% 16% - Pulmonary hypertension 18% 3% < 0.001 - CLAD 16% 2% - others 4% 19% Type of LTx - Double-LTx 92% 81% - Single-LTx 5% 18% < 0.001 - Heart-Lung Tx 3% 1% 36

Bridge to Lung Transplant Survival IPF CF PPH CLAD survival 37

Comparison of Bridged Pts to LTx w/o Bridging Survival after LTx Survival after Re-LTx LTx without bridging bridged to LTx Re-LTx without bridging bridged to Re-LTx 38

Successful ECLS Bridge to LTx 1. Patient Selection 2. Avoid prolonged mechanical ventilation pre- ECLS 3. Provide appropriate pump support 4. Avoid groin cannulation if possible 5. Ambulatory and non intubated preferred (but avoid lung de-recruitment) 6. Nutritional support, consider early tracheostomy 7. Need an engaged AND persistent multidisciplinary team

Take Home Messages ECLS bridge to first lung transplant leads to very good short and long-term outcomes Bridge to re-transplantation requires strict patient selection RAS appears to be a higher risk group Successful bridging is associated with ambulation and weaning from mechanical ventilation 40