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Advances in Lung Transplantation “The best preservation solution for the worst graft”

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.

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Advances in Lung Transplantation “The best preservation solution for the worst graft”

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  1. EACTS Postgraduate Courses Session 3: General Thoracic Surgery Sunday, 22 September 2002Monte Carlo, Monaco Advances in Lung Transplantation “The best preservation solution for the worst graft” Dirk Van Raemdonck, MD, PhD, FETCS University HospitalGasthuisberg, Leuven, Belgium

  2. www.dirkvanraemdonck.be This presentation is available online via

  3. Overview • ischemia - reperfusion injury •lung donors • preservation techniques• preservation solutions •reperfusion techniques •conclusions

  4. • ischemia - reperfusion injury •lung donors •preservation techniques•preservation solutions •reperfusion techniques •conclusions

  5. I-R injury (1) Definition • • post-transplant allograft dysfunction• resulting from damage during • ischemia and reperfusion • • = pulmonary reimplantation response

  6. I-R injury (2) 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)

  7. I-R injury (3) 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)

  8. I-R injury (4) 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)

  9. I-R injury (5) 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)

  10. I-R injury (6) 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)

  11. I-R injury (7) Impact • • increased morbidity & mortality • • prolonged ventilation • • prolonged ICU & hospital stay • • increased costs • (King RC. Ann Thorac Surg 2000;69:1681-5)

  12. I-R injury (8) Identified Risk Factors • •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)

  13. I-R injury (9) Early outcome • Ischemia/Reperfusion Injury Severity Score • IRISS • (Thabut G et al. Chest2002;121:1876-1882) •ischemic time (0 – 40 points) •recipient age (0 – 36 points) •PaO2/FiO2 (0 – 80 points) •hemodynamic failure (0 – 18 points)

  14. I-R injury (10) IRISS and mortality in ICU (Thabut G et al. Chest2002;121:1876-1882)

  15. I-R injury (11) Late outcome • Independent • Predictive Factor • For • BOS • (Fiser SM et al. Ann Thorac Surg2002;73:1041-1048)

  16. •ischemia - reperfusion injury •lung donors •preservation techniques•preservation solutions •reperfusion techniques •conclusions

  17. Lung Donors (1) Final Assessment • •bronchoscopy (endotracheal aspiration) • •imaging (recent chest x-ray) • •macroscopy (inspection - palpation) • (Sundaresan S et al. Ann Thorac Surg1993;56:1409-1413) • •gas exchange (pulmonary vein gas analysis) • (Aziz TM et al. Ann Thorac Surg2002;73:1599-1605)

  18. Lung Donors (2) Lung Donor Score • Task Force inPulmonary Committee of ISHLT • (Waddell TK) •donor age •smoking history •PaO2/FiO2 •x-ray findings •bronchoscopic findings

  19. Lung Donors (3) Recipient Outcome • (Pierre AF et al. J Thorac Cardiovasc Surg2002;123:421-427)

  20. •ischemia - reperfusion injury •lung donors • preservation techniques•preservation solutions •reperfusion techniques •conclusions

  21. Techniques (1) Graft Cooling •topical (NHBD) •donor core cooling on CPB •single pulmonary artery flush (Hopkinson DN et al. J Heart Lung Transplant1998;17:525-531)

  22. Techniques (2) Controversies •flushing conditions (T°, volume, pressure) •pulmonary and/or bronchial arteries • anterograde and/or retrograde flush • storage conditions (T°, oxygen, inflation) (Novick RJ et al. Ann Thorac Surg1996;62:302-314) (Kelly RF. J Lab Clin Med2000;136:427-440)

  23. Techniques (3) 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) (Hopkinson DN et al. J Heart Lung Transplant1998;17:525-531)

  24. Techniques (3) Bronchial Arteries • •preservation of bronchial tree • •cannula in isolated aortic segment • •20 - 30 ml/kg • •60 - 100 mm Hg (Steen S. In Messmer K (ed). Progress in Applied Microcirculation, Basel, Karger, 1996, vol 22, 50-60)

  25. Techniques (4) Retrograde Flush • •primary (via left atrial appendage) • (Sarsam MA et al. J Heart Lung Transplant1993;12:494-498) • •secondary (via pulmonary veins) • (Varela A et al. J Thorac Cardiovasc Surg1997;114:1119-1120) • •preimplantation (on back-table) • (Venuta F et al. J Thorac Cardiovasc Surg1999;118:107-114)

  26. Techniques (5) Storage Conditions •low temperature (4°C) •(no hyper)inflation (15-20 cm H20) •oxygen reserve (FiO2 50%)

  27. •ischemia - reperfusion injury •lung donors •preservation techniques• preservation solutions •reperfusion techniques •conclusions

  28. Solutions (1) Controversies • colloid or cristalloid • intracellular or extracellular

  29. Solutions (2) 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)

  30. Solutions (3) 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 (Kimblad PO et al. Ann Thorac Surg1991;52:523-528)

  31. Solutions (4) Types IntracellularExtracellular • modified Euro-Collins (EC)• Perfadex (LPDG) • University of Wisconsin (UW)• Celsior• Wallwork

  32. Solutions (5) Survey • • 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)

  33. Solutions (6) Electrolytes • (mmol/L) m-EC UW Perfadex Celsior • Na 10 28 138 100 • K 115 125 6 15 • Cl 15 0 142 41.5 • Mg 4 5 0.8 13 • Ca - - 0.3 0.26 • pH 7.4 7.6 7.4 7.3 • mOsm/l 375 327 292 320

  34. Solutions (7) Buffer • (mmol/L) m-EC UW Perfadex Celsior • HCO3 10 5 - - • SO4 - 4 0.8 - • PO4 57.5 25 0.8 - • Histidine - - - 30

  35. Solutions (8) Impermeants (mmol/L) m-EC UW Perfadex Celsior mannitol - - - 60 lactobionate - 100 - 80 raffinose- 30 - - glucose 214 - 5 -

  36. Solutions (9) Oncotic agents (gm/L) m-EC UW Perfadex Celsior Dextran-40 - - 50 - Pentastarch - 50 - -

  37. Solutions (10) Anti-Oxydants (mmol/L) m-EC UW Perfadex Celsior Glutathione - 3- 3

  38. Solutions (11) Energy Precursors (mmol/L) m-EC UW Perfadex Celsior Adenosine - 5 - - Glutamate - - - 20

  39. Solutions (12) Comparative Studies (1) • 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)

  40. Solutions (13) Comparative Studies (2) • UW versus Celsior • (D’ArminiAM et al. J HeartLungTransplant2001:20:183) • • 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

  41. Solutions (14) Comparative Studies (3) EC versus Perfadex (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

  42. Solutions (15) Comparative Studies (4) EC versus Perfadex (1) (RegaF et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002) A-aDO2 p < 0.001 p = 0.59

  43. p = 0.2 p = 0.66 p = 0.17 Solutions (16) Comparative Studies (4) EC versus Perfadex (2) (RegaF et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002) Freedom fromAcute Rejection

  44. p = 0.92 p = 0.59 * p < 0.01 Solutions (17) Comparative Studies (4) EC versus Perfadex (3) (RegaF et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002) Early Survival

  45. Solutions (18) Comparative Studies (5) EC versus UW versus Celsior versus Papworth (ThabutG 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

  46. •ischemia - reperfusion injury •lung donors •preservation techniques•preservation solutions •reperfusion techniques •conclusions

  47. Reperfusion Controlled Conditions •controlled reperfusion (Bhabra MS et al. Ann Thorac Surg1998;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 Surg2002 in press)

  48. 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)

  49. Acknowledgments • Dr F. Rega, research fellow • Leuven Lung Transplant Group (www.longtransplantatie.be)

  50. Thank you for your attention www.dirkvanraemdonck.be

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