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EACTS Postgraduate Courses Session 3: General Thoracic Surgery Sunday, 22 September 2002 Monte Carlo, Monaco. Advances in Lung Transplantation “The best preservation solution for the worst graft”. Dirk Van Raemdonck, MD, PhD , FETCS. University Hospital Gasthuisberg , Leuven, Belgium. - PowerPoint PPT Presentation
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EACTS 16th Annual MeetingMonte Carlo
Advances in Lung Transplantation
“The best preservation solution for the worst graft”
University Hospital Gasthuisberg, Leuven, Belgium
Dirk Van Raemdonck, MD, PhD,
FETCS
EACTS Postgraduate Courses
Session 3: General Thoracic Surgery
Sunday, 22 September 2002
Monte Carlo, Monaco
EACTS 16th Annual MeetingMonte Carlo
www.dirkvanraemdonck.be
This presentation is available online via
EACTS 16th Annual MeetingMonte Carlo
Overview
• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
EACTS 16th Annual MeetingMonte Carlo
• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
EACTS 16th Annual MeetingMonte Carlo
Definition
• post-transplant allograft dysfunction
• resulting from damage during
ischemia and reperfusion
• = pulmonary reimplantation response
I-R injury (1)
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Incidence
• unpredictable
• 57% - 97% perihilar edema(Khan S. Chest 1999:116:187-94)(Anderson D. Radiology 1995:195:275-81)
• 10 - 20 % clinically significant(Zenati M. Transplantation 1990;50:165-67)
• 2 - 5% mortality(Hosenpud J. J Heart Lung Transplant 1996;15:655-74)(Meyers B. Ann Surg 1999;230:362-71)
I-R injury (2)
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Clinical Manifestation
• poor oxygenation (low PaO2/FiO2 - high A-a DO2)
• low pulmonary compliance (Cdyn)
• interstitial / alveolar edema (fluid loss)
• pulmonary infiltrates (injury score on CXR)
• increased vascular resistance (PVR)
• intrapulmonary shunt (QS/QT)
• acute alveolar injury (DAD)
I-R injury (3)
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Mechanisms
• complex (myriad cellular and molecular events)
• endothelial cell dysfunction(increased microvascular permeability)
• alveolar type II cell dysfunction
(pulmonary surfactant alterations)
(Novick RJ. Ann Thorac Surg 1996;62:302-14)
I-R injury (4)
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Differential Diagnosis
• hyperacute rejection(Frost AE. Chest 1996;110:559-62)
• early infection
(Paradis IL. J Heart Lung Transplant 1992;11:S232-6)
• venous anastomotic obstruction(Leibowitz D. J Heart Lung Transplant 1994;13:S39)
• cardiogenic edema (left ventricular failure)
I-R injury (5)
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Treatment • increased ventilation (FiO2 - PEEP) • negative fluid balance (diuretics)
• pulmonary vasodilation (PG - inhaled NO)(Aoe M. Ann Thorac Surg 1994;58:655-61)(Adatia I. Ann Thorac Surg 1994;57:1311-8)
• surfactant replacement (nebulized synthetic)(Struber M. Intensive Care Med 1999;25:862-4)
• extracorporeal oxygenation (ECMO)(Meyers B. J Thorac Cardiovasc Surg 2000;120:20-8)
• urgent retransplantation(Novick RJ. Ann Thorac Surg 1998;65:227-34)
I-R injury (6)
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Impact
• increased morbidity & mortality
• prolonged ventilation
• prolonged ICU & hospital stay
• increased costs
(King RC. Ann Thorac Surg 2000;69:1681-5)
I-R injury (7)
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Identified Risk Factors
I-R injury (8)
• donor-related- quality donor lung (age, cause of death, ventilation)
(Sundaresan S. J Thorac Cardiovasc Surg 1995;109:1075-80)
• preservation-related- preservation solution?- ischemic time?
• recipient-related- pulmonary hypertension
(Bando K. Ann Thorac Surg 1994;58:1336-42)- cardio-pulmonary bypass
(Francalancia N. J Heart Lung Transplant 1994;13:498-57)
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I-R injury (9)
Early outcome
• ischemic time (0 – 40 points)
• recipient age (0 – 36 points)
• PaO2/FiO2 (0 – 80 points)
• hemodynamic failure (0 – 18 points)
Ischemia/Reperfusion Injury Severity Score
IRISS
(Thabut G et al. Chest 2002;121:1876-1882)
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IRISS and mortality in ICU
I-R injury (10)
(Thabut G et al. Chest 2002;121:1876-1882)
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I-R injury (11)Late outcome
Independent
Predictive Factor
For
BOS
(Fiser SM et al. Ann Thorac Surg 2002;73:1041-1048)
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• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
EACTS 16th Annual MeetingMonte CarloFinal Assessment
• bronchoscopy (endotracheal aspiration)
• imaging (recent chest x-ray)
• macroscopy (inspection - palpation)
(Sundaresan S et al. Ann Thorac Surg 1993;56:1409-1413)
• gas exchange (pulmonary vein gas analysis)
(Aziz TM et al. Ann Thorac Surg 2002;73:1599-1605)
Lung Donors (1)
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Lung Donor Score
Lung Donors (2)
• donor age
• smoking history
• PaO2/FiO2
• x-ray findings
• bronchoscopic findings
Task Force in Pulmonary Committee of ISHLT(Waddell TK)
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Lung Donors (3)
(Pierre AF et al. J Thorac Cardiovasc Surg 2002;123:421-427)
Recipient Outcome
EACTS 16th Annual MeetingMonte Carlo
• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
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Techniques (1)
Graft Cooling
• topical (NHBD)
• donor core cooling on CPB
• single pulmonary artery flush
(Hopkinson DN et al. J Heart Lung Transplant 1998;17:525-531)
EACTS 16th Annual MeetingMonte CarloControversie
s • flushing conditions (T°, volume, pressure)
• pulmonary and/or bronchial arteries
• anterograde and/or retrograde flush
• storage conditions (T°, oxygen, inflation)
Techniques (2)
(Novick RJ et al. Ann Thorac Surg 1996;62:302-314)(Kelly RF. J Lab Clin Med 2000;136:427-440)
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Flushing Conditions
• high volume (60 ml/kg) - high rate (4 min)
• low PA pressure (10 – 15 mm Hg)
• low temperature (4°C - 8°C)
• ventilation (VT 10 ml/kg; PEEP 5 cm H2O)
• vasodilator (PGE1 - PGI2 - Nitroglycerine)
Techniques (3)
(Hopkinson DN et al. J Heart Lung Transplant 1998;17:525-531)
EACTS 16th Annual MeetingMonte CarloBronchial
Arteries• preservation of bronchial tree
• cannula in isolated aortic segment
• 20 - 30 ml/kg
• 60 - 100 mm Hg
Techniques (3)
(Steen S. In Messmer K (ed). Progress in Applied Microcirculation,Basel, Karger, 1996, vol 22, 50-60)
EACTS 16th Annual MeetingMonte CarloRetrograde
Flush• primary (via left atrial appendage)(Sarsam MA et al. J Heart Lung Transplant 1993;12:494-498)
• secondary (via pulmonary veins)(Varela A et al. J Thorac Cardiovasc Surg 1997;114:1119-1120)
• preimplantation (on back-table)(Venuta F et al. J Thorac Cardiovasc Surg 1999;118:107-114)
Techniques (4)
EACTS 16th Annual MeetingMonte CarloStorage
Conditions
• low temperature (4°C)
• (no hyper)inflation (15-20 cm H20)
• oxygen reserve (FiO2 50%)
Techniques (5)
EACTS 16th Annual MeetingMonte Carlo
• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
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Controversies
• colloid or cristalloid
• intracellular or extracellular
Solutions (1)
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Colloid or Crystalloid ?
• colloid (donor blood):+ natural: buffer - substrates - scavengers- preparation prior to organ retrieval
• crystalloid :+ simple method, minimum equipment+ technique applicable to any cristalloid+ wash out of harmful blood constituents+ no interference with other teams- embolization of microvasculature (Mg)
Solutions (2)
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Intracellular or Extracellular?
• high K :+ minimize transmembrane ion shift - reflex pulmonary vasoconstriction - endothelial cell damage/permeability
• low K :+ better distribution of flush solution+ uniform cooling of the graft+ lower PVR upon reperfusion+ less hydrostatic edema
Solutions (3)
(Kimblad PO et al. Ann Thorac Surg 1991;52:523-528)
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Types
IntracellularIntracellular ExtracellularExtracellular
• modified Euro-Collins (EC) • Perfadex (LPDG)
• University of Wisconsin (UW) • Celsior
• Wallwork
Solutions (4)
EACTS 16th Annual MeetingMonte CarloSurvey
• colloid:
• donor blood (Wallwork - Papworth) (7%)
• crystalloid:
• modified Euro-Collins (m-EC) (78%)
• University of Wisconsin (UW) (15%)
(Hopkinson DN et al. J Heart Lung Transplant 1998;17:525-531)
Solutions (5)
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Electrolytes (mmol/L) m-EC UW Perfadex Celsior
Na 10 28 138 100 K 115 125 6 15 Cl 15 0 142 41.5Mg 4 5 0.8 13Ca - - 0.3 0.26
pH 7.4 7.6 7.4 7.3mOsm/l 375 327 292 320
Solutions (6)
EACTS 16th Annual MeetingMonte CarloBuffe
r
(mmol/L) m-EC UW Perfadex Celsior
HCO3 10 5 - -
SO4 - 4 0.8 -
PO4 57.5 25 0.8 -
Histidine - - - 30
Solutions (7)
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Impermeants
Solutions (8)
(mmol/L) m-EC UW Perfadex Celsior
mannitol - - - 60lactobionate - 100 - 80
raffinose - 30 - -
glucose 214 - 5 -
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Oncotic agents
Solutions (9)
(gm/L) m-EC UW Perfadex Celsior
Dextran-40 - - 50 -Pentastarch - 50 - -
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Anti-Oxydants
Solutions (10)
(mmol/L) m-EC UW Perfadex Celsior
Glutathione - 3 - 3
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Energy Precursors
Solutions (11)
(mmol/L) m-EC UW Perfadex Celsior
Adenosine - 5 - -Glutamate - - - 20
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Comparative Studies (1)
Solutions (12)
EC versus UW
(Hardesty R et al. J Thorac Cardiovasc Surg 1993:105:660-6)
• historical comparison, non-randomized study (n = 100)
• EC: n= 30 >< UW n = 70
• no differences (longer ischemic times UW)
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Solutions (13)
Comparative Studies (2)
UW versus Celsior
(D’Armini AM et al. J Heart Lung Transplant 2001:20:183)
• randomized study (n = 20)
• UW: n= 10 >< Celsior: n = 10
• A-aDO2 up to 24 hours better (p<0.05) in UW
• no other differences
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Solutions (14)
EC versus Perfadex
Comparative Studies (3)
(Müller C et al. Transplantation 1999;68:1139-43)(Strüber M et al. Eur J Cardiothorac Surg 2001;19:190-194)
(Fischer S et al. J Thorac Cardiovasc Surg 2001;121:594-596)
• 3 historical comparative, non-randomized studies
• EC: ~ n= 50 >< Perfadex: ~ n = 50
• better (p < 0.05) early graft function in Perfadex group
• better (NS) early survival in Perfadex group
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Solutions (15)
EC versus Perfadex (1)
Comparative Studies (4)
(Rega F et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002)
166±12182±13212±18
249±22
309±19
174±9
164±11128±10135±10145±10
168±14
234±20
0
100
200
300
400
Donor Arrival ICU 12 h 24 h 36 h 48 h Time
mm HgEC (n = 49)
LPDG (n = 50)A-aDO2
p = 0.59
p < 0.001
EACTS 16th Annual MeetingMonte Carlo
Solutions (16)
5257,1
85,8
74,4
5041,03
0
10
20
30
40
50
60
70
80
90
100
30 d 6 months 1 year
Time
%
LPDG (n = 50)
EC (n = 49)
EC versus Perfadex (2)
Comparative Studies (4)
(Rega F et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002)
Freedom from
Acute Rejectionp = 0.2
p = 0.66p = 0.17
EACTS 16th Annual MeetingMonte Carlo
Solutions (17)
EC versus Perfadex (3)
Comparative Studies (4)
(Rega F et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002)
Early Survival
96,0 95,592,3
81,383,389,6
0
20
40
60
80
100
30 days 6 months 1 year
%
LPDG (n = 50)
EC (n = 49)
p = 0.92 p = 0.59 * p < 0.01
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Solutions (18)
EC versus UW versus Celsior versus Papworth
Comparative Studies (5)
(Thabut G et al. Am J Respir Crit Care Med 2001;164:1204-1208)
• French multicenter, non-randomized study (n = 170)
• EC: n = 61 >< UW: n = 24 >< Celsior: n = 21 >< Papworth: n = 64
• lower incidence of reperfusion edema in extracellular solutions
• no difference in 1-month mortality
EACTS 16th Annual MeetingMonte Carlo
• ischemia - reperfusion injury
• lung donors
• preservation techniques
• preservation solutions
• reperfusion techniques
• conclusions
EACTS 16th Annual MeetingMonte Carlo
Reperfusion
Controlled Conditions
• controlled reperfusion(Bhabra MS et al. Ann Thorac Surg 1998;65:187-192)
low PA pressure during first 10 min
- slowly releasing PA clamp- reperfusion on CBP
• controlled ventilation(de Perrot M et al. J Thorac Cardiovasc Surg 2002 in press)
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Conclusions
Best Preservation – Worst Graft
• IR-injury: multifactorial (donor - recipient)
• new techniques (retrograde flush)
• new extracellular solutions (Perfadex - Celsior)
• decreased incidence in reperfusion edema
• more extended donors with less optimal grafts
• better early outcome (less acute rejection)
• better late outcome? (less BOS)
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Acknowledgments
• Dr F. Rega, research fellow
• Leuven Lung Transplant Group
(www.longtransplantatie.be)
EACTS 16th Annual MeetingMonte CarloThank you for your attention
www.dirkvanraemdonck.be
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