Massimo Boffini 42° Corso Nazionale TPM Caserta, 3 - 6 ottobre 2017

1. Caserta, 6 Ottobre 2017
La perfusione degli organi
Prof. Massimo Boffini
SCDU Cardiochirurgia
Università degli Studi di Torino
ASOU Città della Salute e della Scienza - Torino

2. Agenda
 General information
 Ex-vivo Lung Perfusion (EVLP)
 Benefits of EVLP
 Open issues of EVLP
 Conclusions
Laperfusionedegliorgani

3. Preservation
Evaluation
Reconditioning
AIMS OF PERFUSION

4. Preservation
Evaluation
Reconditioning
AIMS OF PERFUSION

5. PRESERVATION
HYPOTERMIA SOLUTIONS
 Metabolism
 Ca overload
 Intracellular acidosis
Energetic molecules supply
Prevention cellular edema
Protection oxydative injury
+
COLD STATIC PRESERVATION

6. PRESERVATION
… however
CSP inhibits cellular metabolism and
eliminates the possibility for substantial
reparative processes
IRI: ISCHEMIA REPERFUSION INJURY

Graft Dysfunction (PGD, PNF, DGF…)
COLD STATIC PRESERVATION

7. PERFUSION AS PRESERVATION

8. Preservation
Evaluation
Reconditioning
AIMS OF PERFUSION

9. Graftfunction
*PGD: primary graft dysfunction
retreival
Cold flush  “active” metabolism
 “passive” metabolism
Temperature
transplant
% of graft function
ischemic t (6-10 h)
PGD* 15%

10. optimal
time
retreival
temp
EVLP
ischemic t (6-10 h)
no Tx
poor
EVLP (4-6 h)
transplant
Graftfunction
Cold flush  “active” metabolism
 “passive” metabolism
% of graft function
 “active” metabolism
 “passive” metabolism

11. Donor
Management
Organ
Procurement
Ex vivo Evaluation
Cold Static
preservation
DeclineTransplantation
DECISION
PARADIGM SHIFT

12. SETTING OF EVALUATION
Marginal RejectedStandard
DBD DCD
Controlled Uncontrolled
DONOR

13. SETTING OF EVALUATION
Marginal RejectedStandard
DBD DCD
Controlled Uncontrolled
DONOR
EVLP MANDATORY

14. SETTING OF EVALUATION
MarginalStandard
DBD DCD
Controlled
DONOR
EVLP Recommended
Rejected Uncontrolled

15. SETTING OF EVALUATION
MarginalStandard
DBD DCD
Controlled
DONOR
EVLP not necessary
Rejected Uncontrolled

16. Slama A. et al. J Heart Lung Transplant 2017;36:744–753
4139
“…EVLP might be able to
identify a certain number of
otherwise unrecognized
donor allograft problems…”
2

17. EGA post-oss.
20 min
FiO2 1
Tidal 10
RR 10
PEEP 5
I:E 1:3
Recruitment
25 x 4 sec
1 h
EGA pre-oxy
EGA post-oxy
Compliance
Lung X-Ray
PAP
LAP
55 min
FiO2 0,21
Tidal 6
RR 6
PEEP 5
I:E 1:3
Refresh of
500 ml Steen
61 min
Bronchoscopy
30 min
FiO2 0,21
Tidal 6
RR 6
PEEP 5
I:E 1:3
25 min
FiO2 1
Tidal 10
RR 10
PEEP 5
I:E 1:3
Recruitment
25 x 4 sec
2 h
115 min
FiO2 0,21
Tidal 6
RR 6
PEEP 5
I:E 1:3
Refresh of
250 ml Steen
121 min
Bronchoscopy
90 min
FiO2 1
Tidal 10
RR 10
PEEP 5
I:E 1:3
Recruitment
25 x 4 sec
3 h
175 min
FiO2 0,21
Tidal 6
RR 6
PEEP 5
I:E 1:3
Refresh of
250 ml Steen
181 min
FiO2 1
Tidal 10
RR 10
PEEP 5
I:E 1:3
Recruitment
25 x 4 sec
4 h
235 min
FiO2 0,21
Tidal 6
RR 6
PEEP 5
I:E 1:3
Refresh of
250 ml Steen
241 min
5 e 6 h
Bronchoscopy
210 min
EGA pre-oxy
EGA post-oxy
Compliance
PAP
LAP
EGA pre-oxy
EGA post-oxy
Compliance
Lung X-Ray
PAP
LAP
EGA pre-oxy
EGA post-oxy
Compliance
PAP
LAP
EVALUATION TIMETABLE

18. Preservation
Evaluation
Reconditioning
AIMS OF PERFUSION

19. IN THE DONOR, BEFORE EVLP
Ingemansson R. et al. Ann Thorac Surg 2009;87:255–60

20. EX SITU, AFTER EVLP
Ingemansson R. et al. Ann Thorac Surg 2009;87:255–60

21. CLASSIFICATION OF PERFUSION
In situ / Ex situ
During transfer / Remote
Hypotermic / Normothermic
Cellular / Acellular
Device / “Home-made”
Short/Prolonged perfusion

22. TYPE OF TRANSPLANT
Heart
Lung
Liver
Kidney

23. TYPE OF TRANSPLANT
Heart
Lung
Liver
Kidney

24. Adult and Pediatric Lung Transplants
Number of Transplants by Year and Procedure Type
5 7 35 74
167
408
708
921
1104
1213
13911389
15121548
1566
17081785
19792018
2228
2582
2809
29493023
3309
3587
38693852
41764098
4218
0
500
1000
1500
2000
2500
3000
3500
4000
4500
NumberofTransplants
Bilateral/Double Lung
Single Lung
NOTE: This figure includes only the lung transplants that
are reported to the ISHLT Transplant Registry. As such,
this should not be construed as representing changes in
the number of lung transplants performed worldwide.
2017
JHLT. 2017 Oct; 36(10): 1037-1079

25. SIT – Sistema Informativo Trapianti
* Dati definitivi al 31 Dicembre 2016Fonte dati: Report CRT
Trapianti di POLMONE – Anni 1992-2016*
Incluse tutte le
combinazioni
17
29
33 32
58
83
67
101
60 61 59
65
85
97
93
112
94
112
107
120
114
141
126
112
147
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

26. SIT – Sistema Informativo Trapianti
* Dati SIT al 15 Marzo 2017
Flussi Lista di attesa 1/1/2016 – 31/12/2016
TOTALE PAZIENTI nel periodo dal 1/1/2016 al 31/12/2016
571
Tempo medio di attesa
in lista:
2,4 anni
Pazienti iscritti al 31/12/2016
348
Pazienti USCITI DI LISTA nel
periodo dal 1/1/2016 al
31/12/2016
223
Tempo media di attesa al trapianto: 1 ,5 anni
ISL: 39,2%
ISLT: 25,7%
TRAPIANTI: 147
mortalità in lista: 9,8 %
DECESSI: 56
Altra causa: 20
*ISL: numero TX/Numero iscritti inizio anno
Polmone Pazienti iscritti al
1/1/2016
375
Ingressi in lista nel periodo dal
1/1/2016 al 31/12/2016
196

27. DONATION RATE IN EUROPE

28. Source: Transplant activity in the UK, 2016-2017, NHS Blood and Transplant
Donation and transplantation rates of organs from DBD organ donors in the UK,
1 April 2016 – 31 March 2017
1 Hearts – in addition to age criteria, donors who died due to myocardial infarction are excluded
Bowels – in addition to age criteria, donors who weigh >=80kg are excluded
0
10
20
30
40
50
60
70
80
90
100
Organs from
actual DBD
donors
Donor age
criteria met
Consent for
organ donation
Organs offered
for donation
Organs retrieved
for transplant
Organs
transplanted
Percentage
Kidney Liver Pancreas Bowel Heart Lungs
% of all
organs
% of all organs
meeting age
criteria1
85%
81%
21%
21%
16%
85%
81%
30%
27%
20%
1
Transplanted:
2% 5%

29. Source: Transplant activity in the UK, 2016-2017, NHS Blood and Transplant
Donation and transplantation rates of organs from DBD organ donors in the UK,
1 April 2016 – 31 March 2017
1 Hearts – in addition to age criteria, donors who died due to myocardial infarction are excluded
Bowels – in addition to age criteria, donors who weigh >=80kg are excluded
0
10
20
30
40
50
60
70
80
90
100
Organs from
actual DBD
donors
Donor age
criteria met
Consent for
organ donation
Organs offered
for donation
Organs retrieved
for transplant
Organs
transplanted
Percentage
Kidney Liver Pancreas Bowel Heart Lungs
% of all
organs
% of all organs
meeting age
criteria1
85%
81%
21%
21%
16%
85%
81%
30%
27%
20%
1
Transplanted:
2% 5%
Donor management
Graft manipulation

30. Protective strategy
Tidal volumes 6-8 mL/kg
PEEP 8-10 cm H2O
Closed circuit for tracheal suction
Conventional strategy
Tidal volumes 10-12 mL/kg
PEEP 3-5 cm H2O
Open circuit for tracheal suction

31. RATE OF LUNG
TRANSPLANTABILITY
Despite all improvements in donor management and
organ preservation, still only about 20% of potential
candidate lungs for transplantation are being transplanted
Punch JD, et al. Am J Transpl 2007;7:1327–38.

32. Ex vivo lung evaluation developed and used for
the first time in humans when a lung from a NHBD
was transplanted by Steen in Lund, Sweden*
*Steen S, et al. Lancet 2001;357:825–9.
The first human single lung transplantation of an
initially rejected donor lung, after reconditioning
ex vivo, was successfully performed in 2005**
**Steen S, et al. Ann Thorac Surg 2007;83:2191–5.
It allows
PRESERVATION, EVALUATION, RECONDITIONING
EX VIVO LUNG PERFUSION

33. NEJM April 2011

34. TORONTO PROTOCOL

35. STEEN SolutionTM contains
Human Serum Albumin
Provides normal oncotic pressure preventing oedema
formation
Dextran
a mild scavenger which coats and protects endothelium from
subsequent excessive leucocyte interaction and
thrombogenesis
Extra-cellular electrolyte composition (lowK+)
reduces free radical generation and avoids vascular spasm
under normothermic conditions.

39. Machuca T et al. J Thorac Dis 2014;6(8):1054-1062
INDICATIONS FOR EVLP

40. 1. Successful use of marginal or initially rejected grafts
2. DCD donation
3. An increase of lung transplant activity
4. A better donor/recipient size matching
5. A better evaluation of the graft
6. Better logistics
7. Specific therapies using the perfusion as a reliable platform
EVLP ALLOWS…

41. 1. Successful use of marginal or initially rejected grafts
2. DCD donation
3. An increase of lung transplant activity
4. A better donor/recipient size matching
5. A better evaluation of the graft
6. Better logistics
7. Specific therapies using the perfusion as a reliable platform
EVLP ALLOWS…

42. From July 2011 to April 2017
39 initially rejected lungs underwent EVLP
Mean age 44.03 ± 11.83 (14– 66) years
Gender 24 (61,5%) F/ 15 (38,5%)M
Cause of death 28 (72%) CVA, 6 Trauma, 5 other
Smoke history 14 pts (35,8%)
Mechanical ventilation 4.39 ±2.5 (1 – 10) days
P/F 225.15 ± 100.07 (76 – 512)
26 (66%) positive reconditioning
(25 DLTx + 1 SLTx)
13 (34%) rejected grafts after EVLP
Recondition rate:
66%
EVLP PROGRAM IN TURIN

43. LUNG HISTOLOGY
BEFORE AND AFTER EVLP
EVLP # 4 _PRE EVLP # 4 _POST

44. • July 2011: EVLP program @
University of Turin, Italy
• Toronto Protocol (acellular
solution, low flow perfusion,
closed left atrium)
• Initial experience: similar
incidence of PGD (although
initially rejected grafts used) in
comparison with LTx using
“standard” grafts

45. 78.8
78.17
77.2
77.4
77.6
77.8
78
78.2
78.4
78.6
78.8
79
3 mesi 6 mesi 12 mesi
PaO2 at room air (mmHg)
499
599
0
100
200
300
400
500
600
700
800
3 mesi 6 mesi 12 mesi 24 mesi
6 MWT (meters)
62.5
78
0
10
20
30
40
50
60
70
80
90
3 mesi 6 mesi 12 mesi 24 mesi
FEV 1 (%)
PULMONARY FUNCTION AND EXERCISE TOLERANCE OF LUNG TRANSPLANTED
PATIENTS WITH INITIALLY REJECTED GRAFTS RECONDITIONED WITH EX-VIVO LUNG
PERFUSION (EVLP): MEDIUM TERM RESULTS
M. Boffini, D. Ricci, E. Simonato, F. Scalini, E. Mancuso, R. Bonato, V. Fanelli, M. Ribezzo, M. Attisani, P. Solidoro, M. Ranieri, M. Rinaldi.
Surgical Sciences Department, Cardiac Surgery Division, University of Turin, Turin, Italy.

46. 1. Successful use of marginal or initially rejected grafts
2. DCD donation
3. An increase of lung transplant activity
4. A better donor/recipient size matching
5. A better evaluation of the graft
6. Better logistics
7. Specific therapies using the perfusion as a reliable platform
EVLP ALLOWS…

47. Donor 43 y/o – female
Cause of death: meningitis (Pneumococcus)
6 days of mechanical ventilation
Last P/F: 213
Sputum: Enterococcus spp
CXR & CT Scan: negative for pneumonia

48. 1. Successful use of marginal or initially rejected grafts
2. DCD donation
3. An increase of lung transplant activity
4. A better donor/recipient size matching
5. A better evaluation of the graft
6. Better logistics
7. Specific therapies using the perfusion as a reliable platform
EVLP ALLOWS…

49. HUB AND SPOKE MODEL
“... the concept of taking an injured organ from a donor center, transporting it to
a specialized center for organ assessment and repair, and then once the repaired
organ is suitable for transplant, transporting it to a center for transplantation
into the recipient. In the authors’ opinion, this heralds the future of
transplantation practice.

50. 1. Successful use of marginal or initially rejected grafts
2. DCD donation
3. An increase of lung transplant activity
4. A better donor/recipient size matching
5. A better evaluation of the graft
6. Better logistics
7. Specific therapies using the perfusion as a reliable platform
EVLP ALLOWS…

51. Donor
Management
Organ
Procurement
Ex vivo Evaluation
Cold Static
preservation
DeclineTransplantation
DECISION
PARADIGM SHIFT

52. Donor Management
Organ Procurement
Ex vivo Evaluation
Cold Static preservation
Decline
Transplantation
Ex vivo Organ
Specific Injury Repair
DECISION
Flow Chart – EVLP
What’s next?

53. Ex Vivo
Perfusion
Evaluation Treatment Resuscitation
• Stable and reliable ex vivo maintenance
perfusion technique the treatment platform;
• Reliable lung evalutation;
• Development of a “Treatment Arsenal”
Flow Chart – EVLP
How do we get there?

54. EVLP
What’s next?
• SPECIFIC INJURY TREATMENT (thrombolysis,
antibiotics, surfactant…)
• REMOVAL OF INFLAMMATORY RESPONSE
• GENE THERAPY

55. DONOR
17 y/o, F
173 cm x 50 Kg
oral contraceptives
2 cardiac arrests
P/F 512 mmHg
Chest X-ray: clear
Echocardiogram: moderately dilated
right atrium, severely dilated right
ventricle, PAPs 60 mmHg.
CT scan: bilateral TEP
EVLP (100000UI + 150000UI of
urokinase)
Target flow: 1,68 L/min (40% of the
estimated physiologic cardiac output)
EVLP #38

56. EVLP plus Urokinase
21
18
17
15 15
10
12
14
16
18
20
22
1 2 3 4 5
PULMONARY ARTERY PRESSURE
hours
mmHg
PULMONARY VASCULAR RESISTANCE
11.3
9.5
8.9
7.1 7.1
6
7
8
9
10
11
12
1 2 3 4 5
hours
UW

57. RECIPIENT:
57 y/o, F
Pulmonary Fibrosis
End-stage respiratory
insufficiency
Waiting list: 1664 days
LEFT SLTx, off-pump
Mechanical ventilation 12 h
ICU stay 3 days
Hospital stay 21 days
Warfarin
PRE-OP
POST-OP
LEFT SINGLE LUNG TRANSPLANT
PRE-OP
POST-OP

58. Lungs returned with concern of infection had
good function during 12h EVLP.
CONCERN
ABOUT INFECTION:
- consolidation;
- purulent secretions.
EVLP (12 hs)
R. Bonato et al. ISHLT Congress 2012
Antibiotics Therapy:
• Azithromycin 500 mg;
• Vancomycin 15 mg/kg of IBW;
• Meropenem 2 g.
Ex Vivo Treatment of Infection in human
donor lungs

59. 0
50
100
150
0h 6h 12h
106CFU/L
Ps Aeruginosa (n=
4)
0
50
100
150
0h 6h 12h
106CFU/L
S Aureus (n= 3)
0
50
100
150
0h 6h 12h
106CFU/L
St Maltophilia (n= 3)
0
20
40
60
80
100
0h 6h 12h
106CFU/L
Trichosporon (n= 3)
0
2
4
6
0h 6h 12h
106CFU/L
E Coli (n= 2)
0
50
100
150
0h 6h 12h
106CFU/L
Enterobacter (n= 1)
Change in bacteria level overtime during EVLP.
Promising therapy for rescue infected lungs.
Ex Vivo Treatment of Infection in human
donor lungs
R. Bonato et al. ISHLT Congress 2012

60. 1. Mechanism of action
2. Best Protocol (acellular / cellular perfusion; open
/ closed circuit; duration of perfusion; immediate
/ late perfusion)
1. Evaluation of positive reconditioning
2. Potential bronchus ischemia
1. Graft manipulation
2. Costs
EVLP: OPEN ISSUES

61. Conclusions
 Novel technologies
 Significant role in all solid organ tx
 Transplant scenario rapidly changing
 “Organ-specific” criteria for tx are changing
 Crucial role in DCD donation
 Platform for organ repair
Laperfusionedegliorgani

62. Cattedra di Cardiochirurgia
UNIVERSITA’ DEGLI STUDI DI TORINO
ASOU CITTA’ DELLA SALUTE E DELLA SCIENZA
PROGRAMMA DI TRAPIANTO ORGANI TORACICI
Direttore: Prof. M. Rinaldi
Cardiochirurgia
Prof. M. Boffini
Dott. D. Ricci
Dott.ssa S. El Qarra
Dott. M. Attisani
Dott. C. Barbero
Dott. A. Pellegrini
Dott. E. Simonato
Chirurgia Toracica
Prof. A. Oliaro
Dott. P. Lausi
Anestesia e Rianimazione
Prof. L. Brazzi
Dott.ssa A. Trompeo
Dott.ssa D. Pasero
Dott. A. Sales
Dott. V. Fanelli
Dott. A. Costamagna
Direzione Sanitaria
Dott. A. Scarmozzino
Pneumologia
Prof.ssa Bucca
Dott. P. Solidoro
Dott.ssa D. Libertucci
Dott.ssa L. Mercante
Malattie Infettive
Prof. Di Perri
Prof. F. De Rosa