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Sandro Sponga, MD, PhD
CardioThoracic Dept.
Udine University Hospital
Italy
ACQ Congress
Florence 02 May 2017
Ex-vivo Cardiac Preservation
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December 3, 1967
Louis Washkansky
1° allogenic man-to-man
transplant
Jean-Francois Borel
Cyclosporine
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Machine Perfusion
Cardiac Preservation
LifeCradle®
(Organ Transport Systems, Houston, Texas)
Heart Transporter™ (Organ Recovery Systems, Des Plains, Illinois)
OCS
Organ Care System™ (Transmedics, Andover, Massachusetts)
Cardiac Reconditioning
Graft Evaluation Graft Manipulation
Cold Warm
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• No contemporary evidence of any successful
clinical heart transplant with this strategy
• There is historical evidence for ex-situ
transportable hypothermic perfusion with 4
successful transplants from standard criteria
DBD donors (Cape Town, SA)
Hypothermic Blood Perfusion
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Historical Hypothermic Blood Perfusion
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Annals of Surgery 1973 178:687
Non-pulsatile, low pressure, asanguinous cold perfusion (3 ºC)
No intracellular oedema
Interstitial oedema did not correlate with graft survival
Historical Hypothermic Blood Perfusion
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Historical Hypothermic Blood Perfusion
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Hypothermic Blood Perfusion: devices
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Hardesty, Griffith, et. al
Univ. of Pittsburgh Medical Center
Robicsek, et. al
Charlotte Memorial Hospital
Historical Warm Blood Perfusion
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Historical Warm Blood Perfusion
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Organ Care System console • Easy to use
• Function > 20 hr with 6 batteries
• Robust & Lightweight
• Portable
Heart Solution Set Infused into blood circulation in order to optimize heart perfusion
Heart Perfusion Module •Advanced sterile circuit designed for biocompatibility
•Integrated components enable single motion installation
•Contains reliable pre-calibrated sensors
•Seamlessly integrates between 2 operating modes
•Enables sterile Arterial / Venous blood sampling
Wireless Monitor Controls and Displays all aspects of heart perfusion
Transmedics Organ Care System™
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Remote area organs recruitment
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Transmedics Organ Care System™
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OCS – How it works?
• Haemodynamic ECG, Heart Rate (HR)
Aortic Pressure (AOP)
Coronary Blood Flow (CF)
Aortic Blood Flow (AOF)
Coronary Sinus Saturation
PA Pressure (PAP)
• Metabolic Serial lactate levels
Arterial and venous differential
Pulsatile
Pump
ORGAN CHAMBER
Blood
Warmer
RV Oxygenator
Exit via PA
RA
Blood
Reservoir
AORTA
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Good case Recipient Donor
• 38 yrs, Female, Caucasian
• 170 cm, 70 kg, B Rh +
• HELLP syndrome, Eclampsia, DIC
• CoD: Cerebral Hemorrhage
• Hospital: Lecco
• Hemodynamics:
– SR 95 bpm
– ABP 110/80 mmHg
– Hct 38% (16 PRC, 3000 ml FFP)
• Dopamine 7-8 /kg/min
• Echo
– Normal wall motion/function
– Normal dimension/septum thickness
– Minimal pericardial effusion
• No cath
• Ventilatory support
• 59 yrs, Male, Caucasian
• 170 cm, 67 kg, B Rh +
• Former smoker
• DCM, NYHA Class III
• Medical history:
– Total heart block (PM/ICD, 2004)
– Post-traumatic epilepsy (1993)
– Struma, normal thyroid function (2008)
• Hemodynamics:
– 60 bpm
– ABP 120/70 mmHg
• No ventilatory support, no VAD
• No urgency status
• On WL since 3½ mos
Hemolysis, Elevated Liver enzyme levels and a Low Platelet count
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OCS™ Perfusion Parameters
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
Time (mins)
0
200
400
600
800
1000
AOP (mmHg) HR (BPM) CF (ml/min)
Lactate (mmol/L) A V
1,3
3
1,2
1
1,4
4
1,4
5
1,2
2
1,1
7
1,3
9
1,4
6
1,93
2,08
1,84
2,07
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Intra-operative Course Cardioplegia St Thomas II, 500 cc
CPB time 137 min (54 min assistance)
Off pump first attempt
Hemodynamics ABP 110/60 mmHg, CVP 6 mmHg
No pacing/defibrillation
Intra-op echo normal wall motion/function EDD 45 mm PWD 8 mm
ESD 25 mm IVSD 10 mm
EDV 81 ml EF 74%
ESV 21 ml SF 44%
Inotropes dobutamine 2.4 /kg/min
isoprenaline 0.01 /kg/min
Overall ischemic time
Without OCS™ 443 min
With OCS™ 106 min
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Recipient Donor
• 18 yrs, Female, Caucasian
• 160 cm, 60 kg, 0 Rh +
• CoD: Head trauma (heavy road accident)
• Hospital: Taranto
• Hemodynamics:
– SR 100 bpm
– ABP 125/70 mmHg
– Hct 32%
• Dopamine 5 /kg/min
• Echo
– Normal wall motion/function
EDD 44 mm PWD 11 mm
EF 76% IVSD 11 mm
– No valve pathologies
• No cath
• Ventilatory support
• 59 yrs, Male, Caucasian
• 170 cm, 67 kg, B Rh +
• Former smoker
• DCM, NYHA Class III
• Medical history:
– Total heart block (PM/ICD, 2004)
– Post-traumatic epilepsy (1993)
– Struma, normal thyroid function (2008)
• Hemodynamics:
– 60 bpm
– ABP 120/70 mmHg
• No ventilatory support, no VAD
• No urgency status
• On WL since 3½ mos
Bad case
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OCS™ Perfusion Parameters
0
20
40
60
80
100
120
140
160
180
200
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Time (mins)
AO
P / H
R
0
100
200
300
400
500
600
700
800
900
CF
AOP (mmHg) HR (BPM) CF (ml/min)
2,5
2,8
1
3,7
9
6,3
1 6,6
7,8
1
5,4
6,4
5,0
7 5,7
6,5
1,7
9
2,4
52
,35
2,6
4
3,8
5
4,9
7
6,5
1 6,8
7,8
8
1,9
8
Lactate (mmol/L) A V
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Ann Thorac Surg, 2014
Indication to OCS
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OCS: Udine experience
Donor Recipient
OCS time Cold
Isch.time Tot
Isch time Age Risk Factors Age Risk factors
1 34 58 150 103 253
2 38 HELLP sdr 59 330 105 435
3 46 CAD 43 Redo 88 194 282
4 52 59 174 134 308
5 54 54 ECMO 306 110 416
6 57 CAD, age 62 209 126 335
7 38 Cardiac arrest Expected IT > 5h
51 306 116 422
8 57 Age 58 148 131 379
9 33 Prolonged cardiac arrest 60 355 158 513
10 45 Expected IT > 5h 57 ECMO 388 130 518
11 50 Expected IT > 5h 57 ECMO 350 134 484
12 43 Expected IT > 5h + cardiac arrest 59 Infected LVAD+
Emergency 305 120 425
13 44 Espected IT >5 h 58 Infected LVAD
Emergency 287 138 425
14 39 Cardiac arrest, Troponine, DIC, liver failure 66 ECMO, Redo Emergency
115 80 195
15 45 Expected IT > 5 h 58 ECMO
Mean time 261,23 130,69 399,62
HELLP: Hemolysis, Elevated Liver enzymes, Low Platelet count
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Non utilised graft
RCA traumatic dissection 2007
Ephinephrine bolus 2008
Disconnection OCS-Aorta
2011
9 hours out of body time 2012
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- PROCEED II trial: non inferiority study
- Better myocardial preservation has never been demonstrated in humans
with OCS
AIM of the Study Evaluate better myocardial protection with OCS
Propose OCS as gold standard in heart transplantation to prevent
primary graft failure, early mortality, and possibly expand the donor pool
Italian Health Ministry Grant
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Past
Hypothermic anaerobic organ storage organ time up to 4-6 hours
reducing myocardial energy consumption
slowing loss of high-energy substrates.
Current
Few advancements over the past 25 years. Current preservation solutions:
still lead to time dependent ischemia- reperfusion injury
underutilization of the current consented donor pool
unpredictable outcomes
Ischemia Time: the largest modifiable risk factor for Heart
Transplant outcome
0
0,5
1
1,5
2
30 60 90 120 150 180 210 240 270 300 330 360
Ischemia time (minutes)
p < 0.0001
Re
lati
ve
Ris
k 5
-yr
mo
rta
lity
ULT HEART TRANSPLANTS (1/2002-6/2008)
Risk Factors for 1-yr and 5-yr mortality
J Heart Lung Transplant
2008; 27: 937-83
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30 heart donors randomized 1:1
15
Cold storage
15
OCS
Exclusion criteria: borderline donors, controindication to OCS, donors from
Udine
Minimal sample size: 3-5 patients in each group for biologial data
12-20 patients in each group for clinical data
Study design
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Myocardium will be sampled
at time of
organ harvesting,
before implantation
after reperfusion
Blood samples, at declamping time from
CVC, coronary sinus and OCS
Additional procedures
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Clinical data
AIM 1: Clinical outcomes:
-Survival, EGF, ECMO/IABP, PM, ICU stay, Inotropic score -
Haemodynamic data (CI, SAP, PAP, CVP, WP)
-Echocardiographic data (LVEF, RV function, TAPSE)
-Laboratory data (lactate, troponin, CK-MB, BNP)
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9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.05
0.10
0.15
No
rma
lize
d In
ten
sity
Residual
H2O
Referencestandard
1H NMR spectrum of a human bio-fluid
Metabolic data
AIM 2: metabolic outcomes with (1H NMR) spectroscopy :
-metabolic processes (glycolysis, gluconeogenesis, lipid metabolism).
-impaired myocardial energetics (phosphocreatine/ATP ratio and
ATP/inorganic phosphate ratio).
-new perfusion protocols for OCS
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Biological data
AIM 3: Histological outcomes (histology immunofluorescence, cellular,
molecular and electron microscopy (EM):
-ischemia-reperfusion injury
inflammation
autophagy
DNA or cytoplasm damage
rejection
-Sarcomeres, mitochondria and sarcolemma (EM)
-Micro RNA markers of myocardial damage (ST2, miR1, miR133a,
miR133b, miR499-5p, miR122 and miR375)
p16INK4A
DAPI
𝛼SA
gH2A.X
Ki67
DAPI
𝛼SA
gH2A.X
Ki67
DAPI
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A living organ outside the body:
a new unique model
No systemic
adverse effects
High concentration
Long time infusion
Effect limited to the graft
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Virus transfection and
immunotherapy Employing immunotherapy developed for tumor,
antigens exposed by the donor heart can be
modified to reduce rejection
Bodreau et al Molecular Therapy (2011)
Reduction of
Rejection
Infection
Tumor
CAV
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• Gene editing
• Immunogenic modulation
• ↓ acute and chronic rejection
• ↓ Immunosuppression and side effects
• Xenotransplantation
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The old dream ……
xenotransplantation
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The organ factory The organ factory
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Circulatory death:
Italy 20 minutes
Australia 10 min
Canada 5 minutes
USA 5 minutes (Pittsburg
Protocol)
Boucek 75 sec
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Experience with DCD hearts
• Resuscitated human cadaver heart and transplanted it into a baboon
• First heart Tx was technically a DCD donor heart
• 3 DCD hearts used in paediatric heart transplants with good outcomes, all alive at 6 months; Denver, USA
• Human DCD heart successfully resuscitated using extracorporeal perfusion
2008
2009
1966
1967
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DCD inclusion criteria
44
•Maastricht Category III donors
•< Age 40
•No history of cardiac disease, prior cardiac surgery or significant
cardiac trauma
•Low dose inotrope/vasopressor – NA < 0.2 mcg/kg/min
•Stable haemodynamics MAP > 60 and CVP < 10 mmHg
•Maximum warm ischemic time of 30 min
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DCD Protocol
45
• Ischemic time < 30 min
• Transfer to OR
• Very rapid blood retrieval from RAA with dual-stage cannula (better
and rapid drainage and decompression of abdominal organs
• During blood collection aortic cross clamp
• Anterograde perfusion: 1l of ST Thomas cardioplegia
• OCS instrumentation
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47
DCD Retrievals
N=24
Did Not Progress
N = 8
Asystole within
30min
N=16
Not Transplanted
N=5
Poor Lactate
N=3
OCS Failure
N=2
Transplanted
N=11
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DCD Clinical update
•DCD HTx series from St vincents Hospital, Sydney 11 patients
remain well at home with normal biventricular function
•DCD HTx series from Papworth Hospital , Cambridge and
Harefield Hospital, London, UK make a combined DCD
HTx recipient cohort of 37 at end of 2016
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Metabolic
Resuscitation
OCS Optimizes:
Perfusion
Substrate & Hormones
Assessment
OCS Enables:
Metabolic/Perfusion
Functional
Echo coronary Coronary
Coronary angiography
Reduction in
Ischemia
OCS Maintains Hearts in:
Oxygenated perfusion state
Donors
Results
Transmedics Organ Care System
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Thank you
A good head and a good heart are always a formidable combination.
N. Mandela