Marco Schiavon 39° Corso Nazionale TPM Imola, 12-15 aprile 2016

1. “LA MIA ESPERIENZA
INNOVATIVA È: LA PERFUSIONE
DEGLI ORGANI”
Marco Schiavon
Chirurgia toracica
Università degli studi di Padova
Imola 12/15 Aprile 2016

2. The standard of care for preservation of donated lungs
-- a cold flush and static cold storage –
is reasonably good as long as ischemia times aren't
excessive and the organs are of good quality to start with
Hypothermic preservation inhibits cellular metabolism and
eliminates the possibility of substantial reparative
processes occurring after donor organ injury

3. MAY AN EXTENDED/UNSUITABLE
DONOR BECOME AN
“IDEAL/SUITABLE” DONOR?
Some extended criteria may be reversible or managed
before or after lung harvesting (low PaO2, atelectasis,
contusions).
The negative impact on outcome for other criteria (e.g.
age >55 yrs) may be reduced by reducing the cold ischemic
time.
Often the difficulty in using marginal donors derives from
the impossibility to perform a prolonged assessment in
order to distinguish reversible injury from irreversible
alterations

5. EX VIVO LUNG PERFUSION
EVLP

6. FROM THE FIRST REPORTS…
…TO DIFFERENT DEVICES

7. by increasing the acceptance rate
 by decreasing the incidence of PGD (IRI)
 by decreasing the incidence of BOS (CR)
How could EVLP help to improve
outcome?

8. EVLP = Platform for
 Assessment
 Preservation
 Reconditioning
 (Immunomodulation)

9. 1) Ex Vivo Assesment
 Visual
 Physiological
 Biological
 Radiological

10. • Hemodynamics (PVR, PAP, flow)
• Ventilation (AwP, Cdyn)
• Oxygenation (PO2/FIO2; delta PLAO2 - PPAO2)
• Inflammatory markers (cytokines BAL – Bx)
• Cell viability (histology Bx)
• Edema (W/D, EVLW, perfusate volume)
• Radiology (x-ray – CT chest)
Parameters of viability in pulmonary graft?

11. New perspectives: Lung x-ray on portable EVLP

12. CONSOLIDATION AREA WITH
HEMORRHAGIC CONGESTION
DURING EVLP
CONSOLIDATION AREA AT
THE CHEST X RAY DURING
THE EVLP
SINGLE LEFT LUNG
TRANSPLANTATION

14. 2) Ex Vivo Preservation
 shorten cold ischemic time
 prolong cross clamp time
 planned procedure
 day time surgery?
Standard criteria lungs

15. Am J Transplant 2009;9:2262-9

16.  Ischemic injury
 No recruitment
 No assessment
 Delayed benefits
 Resource intensive
 Delayed clinical decision making
Static EVLP Vs. Portable OCS Lung
16
 Reduction of ischemia
 Immediate & sustained recruitment
 Continuous monitoring & assessment of function
 Existing resources and Streamlined decision making
process

17. Lancet 2012:380(9856):1851-8

18. INTERNATIONAL, MULTICENTER, RANDOMIZED ON THE USE OF THE
DEVICE OCS FOR THE PRESERVATION OF THE LUNG
THAT COMPARE
RANDOMIZED POPULATION SCHEDULED: 370 PATIENTS
DONORS PRESERVED WITH OCS
STANDARD COLD STORAGE

19. [OLB05*] THE ORGAN CARE SYSTEM (OCS™) LUNG INSPIRE
INTERNATIONAL TRIAL RESULTS
Abbas Ardehali, Marshall Hertz, Ken Mccurry, Christian Bermudez,
Marco Schiavon, Joren Madsen, Federico Rea, Gabiel Loor, Michael
Smith, Jasleen Kureja, Gregor Warnecke, Dirk Van Raemdonck,
Gilbert Massard, Andre R. Simon, Javier Moradiellos, Andres Varela,
Igor Tudorache, Christian A. Kuehn, Murat Avsar, Wiebke Sommer,
Bettina Wiegmann, Hermann Reichenspurner, Jaya Nagendran,
Pascal A. Thomas, Nicola Santelmo, Pierre E. Falcoz, Anne Olland,
Christoph Knosalla, Roland Hetzer, Steven Tsui, Kumud Dhital, Axel
Haverich
Results: 306 subjects were treated per protocol, 141 OCS group and 165 SOC
group patients. While the total out of body time was longer in the OCS group,
the total ischemia time was significantly shorter vs. SOC group (p<0.001). At
day 30, survival and freedom of PGD 3 within 72 hours was 79.4% of the
OCS vs. 70.3% of SOC patients (Primary effectiveness endpoint: Non-
inferiority p=0.0045 and superiority p=0.09). For the composite of in hospital
survival and freedom of PGD 3 within 72 hours, 80.1% of OCS patients met
the endpoint vs. 66.7% of SOC arm (Non-inferiority p=0.0003 and superiority
p=0.01). Freedom from PGD 3 within the first 72 hours post-transplant was
82.3% in OCS arm vs. 70.3% in the SOC arm (superiority test p= 0.016). The
trial met the primary safety endpoint under the non-inferiority margin of
0.075; p=0.0035.
Conclusions: This trial meets all its non-inferiority endpoints and multiple
important superiority endpoints including a significant reduction of PGD
grade 3 using the OCS Lung technology. These results provide evidence for
new portable EVLP strategies in routine lung preservation to improve
outcomes.
WAITING FOR FINAL RESULTS

20. First lung ischemic time: 13 h 32 min
Second lung ischemic time: 16 h

21. PADUA EXPERIENCE WITH OCS
22 OCS
10 (3 MARGINAL) 11
ENROLLED IN INSPIRE TRIAL OUTSIDE INSPIRE TRIAL
2
VAD-DCD LOBAR CONGESTIONEDEMA
1 1
MARGINAL DONORS (8) IDEAL DONORS (3)
BEFORE INSPIRE TRIAL
P/F < 300 MMHG
2 2
AGE > 55 YEARS AND
POOR RECRUITMENT

22. OUR EXPERICENCE IN STANDARD DONORS
RECIPIENTS AGE
(years)
SEX DIAGNOSIS PAH Emergency
status
Preoperative
ECMO
Recipient 1 60 F IPF Secondary No no
Recipient 2 58 F IPF Secondary No no
Recipient 3 57 M Istiocytosis X Secondary No no
Recipient 4 47 M IPF Secondary No no
Recipient 5 18 F CF No No no
Recipient 6 28 F CF No Yes yes
Recipient 7 22 F CF No Yes yes
Recipient 8 24 M CF No No no
Recipient 9 47 F CF No No no
Recipient 10 34 M CF No No no
Recipient 11 27 F CF Secondary Yes yes
Recipient 12 42 M CF No No no
Recipient 13 62 M IPF Secondary No no
 MEDIAN AGE: 42 YEARS (RANGE 18-62)
 EMERGENCY STATUS: 3 PATIENTS (23.1%), ALL WITH V-V ECMO
 SECONDARY HYPERTENSION: 6 PATIENTS (46.2%)
DIAGNOSIS:
- 8 CYSTIC FIBROSIS
- 3 IPF
- 1 ISTIOCYTOSIS X

23. DONORS CHARACTERISTIC
DONORS AGE
(years)
SEX SMOKE ( >
20 packs/yr)
CAUSE OF
DEATH
FINAL
PaO2/FiO2 at
retrieval
Eurotransplant
SCORE
Oto
SCORE
Donor 1 29 F No Intracranial
bleeding (abscess)
514
6 0
Donor 2 46 F No SAE 488 8 1
Donor 3 56 F Yes SAE 522 8 3
Donor 4 49 M No SAE 434 6 1
Donor 5 13 M No Cerebral anoxia 373 6 0
Donor 6 33 M Yes SAE 342 8 5
Donor 7 39 M No Head trauma 351 6 0
Donor 8 40 F No Meninigitis 425 6 0
Donor 9 27 F No SAE 510 7 0
Donor 10 18 M No Cerebral anoxia 443 6 1
Donor 11 47 F Yes SAE 369 7 5
Donor 12 41 M No Cerebral edema
post-surgery
349 6 4
Donor 13 63 F No SAE 362 9 6
 MEDIAN AGE: 40 YEARS (13 - 63 YEARS)
 SMOKING HISTORY: 3 PATIENTS (23.1%)
 MEAN FINAL PAO2/FIO2: 422 ± 69 mmHg
 MEAN OTO SCORE: 2 (0 – 6)
 MEAN EUROTRANSPLANT SCORE: 7 (6 – 9)

24. Pulmonary vascular resistence trend Peak airway pressure trend
DURING OCS LUNG PRESERVATION
PREHARVEST MEAN PaO2/FiO2 : 422 ± 69 mmHg
AFTER OCS LUNG MEAN PaO2/FiO2: 495.6 ± 69 mmHg
p=0.01
*
VASCULAR RESISTANCE TREND PEAK AIRWAY PRESSURE TREND
 MEAN PRE-INSTRUMENTATION TIME: 74 ± 10 min (6 CASES OF PULMONARY ARTERY RECONSTRUCTION)
 MEAN RUNNING TIME ON OCS: 289 ± 94 min (range 115-445)
 CUMULATIVE COLD ISCHEMIC TIME: 179 ± 22 min (first lung)
296 ± 37 min (second lung)

25. IN-HOSPITAL POSTOPERATIVE DATA
RECIPIENTS Intraoperative
ECMO
Prolonged
post-
operative
ECMO
MV (h) ICU stay
(h)
PGD score
at 0 h
PGD
score at
24 h
PGD
score at
48 h
PGD
score at
72 h
Recipient 1 yes yes <24 > 30 days 0 0 0 2
Recipient 2 yes No 48 > 30 days 0 0 0 0
Recipient 3 yes No <24 120 0 0 0 0
Recipient 4 yes yes <24 168 0 0 0 0
Recipient 5 yes No <24 142 0 0 0 0
Recipient 6 yes yes <24 429 0 2 1 0
Recipient 7 yes yes 72 264 1 0 0 0
Recipient 8 No No <24 96 0 0 0 0
Recipient 9 No No <24 119 2 0 0 0
Recipient 10 no no <24 148 0 0 0 0
Recipient 11 yes yes 24 days >30 days 2 3 2 2
Recipient 12 no no 72 144 1 1 0 0
Recipient 13 yes no 43 days > 30 days 0 1 0 0
 PROLONGED POST-OPERATIVE ECMO: 5 PATIENTS (38.5%) FOR PROPHYLACTIC PURPOSE
 11 PATIENTS (84.6%) WERE EXTUBATED WITHIN 72 H OF TRANSPLANTATION (MEDIAN MV < 24H)
 MEDIAN ICU STAY 158 H (6.6 DAYS)
 NO PGD SCORE 3 AT 72 H

26.  SURVIVAL OF GRAFT AND THE PATIENT AT 30 DAYS: 100%
 2 IN-HOSPITAL DEATHS RELATED TO MDR KLEBSIELLA PNEUMONIAE SYSTEMIC INFECTION
 NO ACUTE REJECTION AT 6 MONTHS
SURVIVAL
RECIPIENTS SURVIVAL
(months)
In hospital
mortality
TBB
Histology at 1
month
TBB
Histology at
3 month
TBB Histology
at 6 month
STATUS
Recipient 1 3 Yes ND ND ND Deceased
Recipient 2 3 Yes A0B0 ND ND Deceased
Recipient 3 32 No A0B0 A0B0 A0B0 At home
Recipient 4 32 No A0B0 A0B0 A0B0 At home
Recipient 5 23 No A2B0 A2B1 A0B0 At home
Recipient 6 23 No A0B0 A0B0 A0B0 At home
Recipient 7 13 No A3B0 A0B0 A0B0 At home
Recipient 8 12 No A2B1 A0B0 A0B0 At home
Recipient 9 8 No A0B0 A0B0 A0B0 Deceased
Recipient 10 11 No A0B0 A0B0 A0B0 At home
Recipient 11 5 No A0B0 A0B0 A0B0 At home
Recipient 12 2 No A2/3B0 A0B0 ND At home
Recipient 13 3 No A0B0 ND ND Hospitalized

27. Lung Ischemia-Reperfusion
A complex pathophysiological process
ISCHEMIA
Hypoxia
Mechanotransduction
Macrophages
Endothelial cells
ROS
Cytokines
REPERFUSION
Neutrophils
Platelets/thrombin
activation
NO-ROS
Interaction
VASCULAR DAMAGE
NADPH
Oxidase
NK-kβ
eNOS/iNOSCell Surface
Molecules
I/R injury
PVR
Pμvas
c
Pulmonary
Edema
Modified from den Hengst 2010

28. HISTOPATHOLOGY OF WARM PERFUSION
VERSUS COLD PRESERVATION OF DONOR
LUNGS
 Lung samples from 34 patients of the INSPIRE trial lung,
transplanted in Padova and Hannover (October 2011 -
November 2014), randomly assigned to two groups
“cold storage” group (SOC) (17) “OCS™ device” group (17)

29. 2 tissue samplings from each donor lung
1) DIMENSION AND SITE
2 cm2
, on the first lung implanted
(preferentially on middle lobe or lingula)
2) TIME:
•FIRST SAMPLING: at the time of back-table after preservation and
immediately before reimplantation
•SECOND SAMPLING: 90 minutes after reperfusion on recipient
3) PRESERVATION
-after sampling: one small piece stored in RNA later
and preserved immediately at 4°C
-the remaining lung tissue stored in buffered formalin
MATERIALS AND METHODS

30. Apoptosis (pre-
reperfusion)
p=ns
Apoptoticindex(%)
Apoptosis (post-
reperfusion)
p=0.05

31. p=0.08
Numberofi-NOSpositiveendothelialcells(%)
i-NOS (pre-reperfusion)
i-NOS (post-reperfusion)

32. No significant “gross” morphological
difference: congestion/edema, blood
extravasation, leukocyte margination
More evident molecular damage: significant
less apoptosis and i-NOS expression ( mainly
at post-reperfusion time) was seen in OCS
lung
i-NOS is an important mediator of I/R
Tissue evaluation summary

33. 3) Ex Vivo Reconditioning
 edema
 infection
 aspiration
 contusion
extended criteria lungs

34.  warm perfusion ~ no vasospasm
 continuous delivery oxygen/nutrients
 active metabolism
 protective ventilation with PEEP
 alveolar and vascular recruitment
 removal waste products- detoxification
 refreshment of perfusate - dilution
Ex Vivo Perfusion

35. Inflammatory BioMarkers
Ann Thorac Surg 2010;89:1773-9

36. Ann Thorac Surg 2010;89:1773-9

37. Ann Thorac Surg 2010;89:1773-9

38.  anti-edema: high osmotic solution / β-adrenergic
agents
 anti-infection: antibiotics / antifungal agents
 anti-inflammation: steroids / anti-oxydants / gene /
gases
 anti-trombotic: heparine / fibrinolytics
Pharmacological Interventions

39. Lung is unique!
 Vascular tree
(pulmonary + bronchial)
 Bronchial tree
Dual Access System for Intervention

41. Reported Clinical Series
on Lung
Transplantation
following EVLP

42. 6 DL
Ann Thorac Surg 2009;87:255-60

43. N Eng J Med 2011;364(15):1431 - 1440
Yield 86%

44. Am J Transplant 2012; 12: 1839-47
Yield 69%

45. Am J Transplant 2012; 12: 1839-47

46. J Thorac Cardiovasc Surg 2012;144:1222-8
Yield 100%

49. Van Raemdonck et al. Transplant Int, 2014

50. Expand trial
• International, multicenter, randomized trial (15
centers)
• Number of planned patients: 55
• Purpose: to evaluate the safety and effectiveness of
the ocs™ lung to recruit, preserve and assess donor
lungs that may not meet current standard donor lung
acceptance criteria for transplantation.

51. Inclusion criteria
- Donor PaO2/FiO2 ≤ 300 mmHg; or
- Expected ischemic time > 6 hours; or
- Donor after Cardiac Death (DCD donor); or
- Donor age ≥55 years old
Exclusion criteria
- Presence of moderate to severe traumatic lung injury with air and/or blood leak
- Presence of confirmed active pneumonia or persistent purulent secretions on repeated
bronchoscopy evaluation or ET suction
- Previous history of pulmonary disease
- Multiple transfusions of >10 pRBCs units
- ABO incompatibility
- Tobacco history of >20 packs per year

52. DCD and EVLP
From pre-clinical study…

53. DCD and EVLP
… to clinical application
Lastly, some groups have moved further with the clinical use of
uncontrolled DCDs. Pioneer work from the Hospital Universitario
Puerta de Hierro has initially shown high incidence of PGD3
(38%), with 17% hospital mortality and 57% 1-year survival from
29 uncontrolled DCD LTxs. The addition of EVLP to this
algorithm helped to better select this lungs and rendered no
case of PGD3 in the initial 4 EVLP LTxs, with additional
exclusion of four lungs with poor EVLP performance.

54. PADUA EXPERIENCE WITH OCS
22 OCS
10 (3 MARGINAL) 11
ENROLLED IN INSPIRE TRIAL OUTSIDE INSPIRE TRIAL
2
VAD-DCD LOBAR CONGESTIONEDEMA
1 1
MARGINAL DONORS (8) IDEAL DONORS (3)
BEFORE INSPIRE TRIAL
P/F < 300 MMHG
2 2
AGE > 55 YEARS AND
POOR RECRUITMENT

55. USE ON MARGINAL DONORS
Anamnesis Cause of death CT scan Bronchoscopy PaO2/FiO2 at
the arterial
blood gas
Eurotransplant
Score
Intraoperatory
findings
A 18 year-old
young female
without any
significant
medical history.
Head and abdominal
trauma due to car
accident.
Pulmonary contusion
in the right upper
lobe and in the
posterior part of the
left upper lobe.
Normal anatomy;
BAL: multi-
sensitive
Pseudomonas A.
-250 mmHg at the
call
-183 mmHg after
lung exploration
-319 mmHg after
recruitment
maneuvers
7 Bilateral edema
PaO2/FiO2
(Continuos monitoring)
FIRST EVALUATION
(1 HOUR)
671
SECOND EVALUATION
(2 HOURS)
476
LAST EVALUATION
(6 HOURS)
571
Instrumentation time: 56 min
OCS running time: 450 min
Ischaemic time:
161 min for right lung
291 for the left side

56. RECIPIENT OUTCOME
25 months

57. • Age: 54 years
• Implant of L-VAD 19 days before retrieval
• History of smoke: < 20 pack-years
• Death cause: ESA
• Mechanical ventilation: 72h
• P/F (Fi O2 100%): 511 mmHg
• Chest X-ray and bronchoscopy: negative
• Eurotransplant score: 10
During retrieval:
-Gentle preparation for strong adhesions
between left lung and the outflow cannula
-During abdominal preparation several
episodes of severe hypotension occurred,
poorly responsive to drugs with risk of
sudden right ventricular failure
-Recipient was not in OR
Lung assessment and
preservation with the Organ Care
System (OCS) Lung in order to:
-Reduce ischemia < 6 hours
-Evaluation of organ after right
heart failure
USE OF OCS LUNG IN A L-VAD DONOR
DONOR

58. CHEST X RAY DURING THE
EVLP SHOWED NORMAL
LUNGS
Post-operative course:
- PGD rate: 3,1,2,0 at T-0, T24, T48 and T72.
-The patient was extubated on day 3
-The patient was discharged on day 33 with an uneventful post-operative course
• Age: 61 years
• Pulmonary disaese: IPF
• OCS lung running time: 340 min
• Final P/F (Fi O2 100%): 525 mmHg
• Chest X-ray and bronchoscopy:
negative
• Total cold ischemic time:
183 min for right lung
292 min for the left side.
RECIPIENT

59. • Donors site: Thessaloniki (Greece)
• Age: 61 years
• History of smoke: none
• Death cause: cerebral ischemia
• Mechanical ventilation: 96 h
• P/F (Fi O2 100%): 483 mmHg
• Chest X-ray: negative
• Bronchoscopy: moderate mucoid
secretions especially on the left side
• Eurotransplant score: 8
DONOR
USE OF OCS LUNG IN A DONOR WITH LOW PAO2
AND LONG ISCHEMIC TIME
RETRIEVAL PHASE
-Normal lung appareance
-Low PaO2/FiO2 rate: 237 mmHg
despite recruitment maneuvers
Lung assessment and
preservation with the Organ Care
System (OCS) Lung in order to:
-Reduce ischemia < 6 hours
-Evaluation of organ for low
PaO2/FiO2 ratio

60. OCS ASSESSMENT
- Improvement of lung parameters: vascular resistance, peak airway
pressure
- Improvement of PaO2/FiO2: 500 mmHg
- Normal lung x-ray appareance
USE OF LUNGS FOR BILATERAL TRANSPLANTATION IN A PULMONARY
FIBROSIS

61. 4) Ex Vivo Immunomodulation
 MSCs?
 blocking APC?

62. Curr Opin Organ Transplant 2013;18:24-31

64. • extensively investigated in different animal models
• clinical applications implemented
• improved quality and utilization donor lungs even in
DCD cases
• portable (OCS) device superior to other static devices
• better recipient outcome (PGD ↓ – BOS ↓)
• multicenter trial to better define technical aspects
Ex Vivo Lung Perfusion (EVLP)
Conclusions

65. PadovaPadova
grazie
Padova