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Primary Graft Dysfunction in Lung Transplantation

Primary Graft Dysfunction in Lung Transplantation. Dr. Ömer Ş enbaklavac ı Department of Thoracic and Cardiovascular Surgery University Hospital Johannes Gutenberg-University Mainz. 15 th Annual Congress of Turkish Thoracic Society, 11-15 April 2012. Primary Graft Dysfunction ( PGD ).

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Primary Graft Dysfunction in Lung Transplantation

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  1. Primary Graft DysfunctioninLung Transplantation Dr. Ömer Şenbaklavacı Department of Thoracic and Cardiovascular Surgery University Hospital Johannes Gutenberg-University Mainz 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  2. Primary Graft Dysfunction ( PGD ) • Primary Graft Failure • Early Graft Dysfunction • Reperfusion Edema • Reperfusion Injury • Re-implantation Response • Re-implantation Edema 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  3. Ischemia/Reperfusion Injury 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  4. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 PGD Characteristics • First hours up to 3 days after LuTX • Poor oxygenation • Low pulmonary compliance • Interstitial / alveolar edema • Infiltrates on chest x-ray • Diffuse alveolar damage on pathology 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  5. United Network for Organ Sharing / ISHLT Registry Between 1994 and 2002 n = 6984 patients Incidence of PGD = 10.7 % (literature 10 to 57 %) 30 day-mortality: Patients with PGD = 34.9 % Patients without PGD = 6.6 % p<0.0001 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  6. n=5262 patients 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  7. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Recommendations for Grading of PGD Severity Grade PaO2/FiO2 Radiographic infiltrates 0 >300 Absent 1 >300 Present 2 200-300 Present 3 <200 Present T0, T24, T48 and T72 e.g. T72 Grade 3 PGD 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  8. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Exclusion Factors Beyond 48 hours following etiologies should be taken into account • Hyperacute rejection • Venous anastomotic obstruction • Cardiogenic pulmonary edema • Pneumonia 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  9. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 PGD Risk Factors • Donor-related risk factors • Recipient-related risk factors 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  10. UNOS/ISHLT Registry (6984 Patients) Kuntz CL,et al. Clin Transplant 2009;23:819-30 Donor-Related Risk Factors • Inherent donor factors • Age • Underlying lung disease • Race • Gender • Smoking history 2. Acquired donor factors • Brain death • Trauma • Prolonged mechanical ventilation • Bronchoaspiration • Pneumonia • Multiple blood transfusions • Hemodynamic instability • Ischemic time • Preservation solution 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  11. UNOS/ISHLT Registry (6984 Patients) Kuntz CL,et al. Clin Transplant 2009;23:819-30 Donor-Related Risk Factors Variable Adjusted OR p-value Donor age>45 yr 1.83 <0.001 Donor cause of death CVA Reference Trauma 1.30 <0.032 Eurocollins solution 1.44 0.001 Ischemic time 1.25 <0.001 (per hour above 3 h) 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  12. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Donor-Related Risk Factors Brain death brain death  neuro-endocrine dysregulation  hemodynamic and inflammatory changes ( ↑ interleukin-8 + ↑ neutrophil infiltration )  lung injury donor head trauma is independent risk factor for PGD (Kuntz CL,et al. Clin Transplant 2009;23:819-830) biopsies from cadaveric kidney donors show higher levels of inflammatory cytokines than from living donors  higher incidence of PGD and acute rejection (Koo DD,et al. Kidney Int 1999;56:1551-9) 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  13. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Donor-Related Risk Factors Hemodynamic instability Low blood pressures hypoxemia excessive fluid administration lung edema ↓energy metabolism 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  14. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Donor-Related Risk Factors Recommendations Methylprednisolon 15 mg/kg after brain-death reduction of inflammatory reaction Fluid restriction with CVP < 10 mm Hg Dopamine + Vasopressin 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  15. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Donor-Related Risk Factors Lung Preservation • Temperature of preservation solution: 4°C • (decreases the metabolic rate to 5% of that at 37°C ) • Volume of preservation solution: 60 ml/kg • Pressure of preservation solution infusion: 10-15 mmHg • Ventilation during lung procurement • Inflation during storage: not more than 50% of total lung capacity to • avoid barotrauma • Oxygenation: ventilation and inflation with FiO2 0.3-0.5 • Storage temperature: 4°C • Preservation solution: extracellular type (Perfadex, LPD, Celsior) is • better than intracellular type (Euro-Collins) • (Thabut G,et al. Am J Respir Crit Care Med 2001;164:1204-8) 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  16. Recipient-Related Risk Factors • United Network for Organ Sharing/ISHLT Registry • Between 1994 and 2002 • n=6984 Patients • Kuntz CL,et al. Clin Transplant 2009;23:819-30 • BMI > 25 kg/m2 • Female gender • Single lung transplant • PAP systolic > 60 mmHg • Indication: primary or secondary pulmonary hypertension • primary or secondary pulmonary fibrosis 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  17. UNOS/ISHLT Registry (6984 Patients) Kuntz CL,et al. Clin Transplant 2009;23:819-30 Recipient-Related Risk Factors Variable Adjusted OR p-value Female gender 1.41 0.001 BMI ≤18 Reference 25 to <30 1.66 0.005 ≥30 1.75 0.006 Systolic PAP (mmHg) ≤30 Reference >60 to ≤ 90 2.06 0.001 >90 2.57 0.002 Single lung transplant 1.44 0.005 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  18. UNOS/ISHLT Registry (6984 Patients) Kuntz CL,et al. Clin Transplant 2009;23:819-30 Recipient-Related Risk Factors Diagnosis OR Adjusted for PASP OR n=5564 n=4026 COPD Reference Reference PPH 4.01 2.38 CF 1.41 1.40 IPF 1.76 1.94 SPH 4.03 2.18 SPF 1.59 2.57 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  19. UNOS/ISHLT Registry (6984 Patients) Kuntz CL,et al. Clin Transplant 2009;23:819-30 Procedure-Related Factors • Re-transplantation: no elevated risk for PGD • Bleeding and transfusion-related lung injury: unclear • Reperfusion technique: controlled reperfusion for 10 min • Role of cardiopulmonary bypass: controversial • CPB  systemic, pro-inflammatory response  • activation of cytokines, leukocytes and complement system 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  20. 386 papers were reviewed • 14 papers represented the best evidence to answer this question • 6 papers showed significantly worse outcomes with CPB • 6 papers showed no difference • 2 papers showed a mixture of both depending on the specific • outcomes assessed 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  21. Question to be answered: Can elective use of CPB avoid the overperfusion of the first implanted lung thus resulting in decreased incidence of PGD? • Sheridan, et al. Ann Thorac Surg 1998;66:1755-8. • 23 DLuTX without CPB • No differences in CXR infiltrate score and quantitative lung perfusion • scan of the initially implanted lung and the second implanted lung. 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  22. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Treatment General Considerations • Avoid excessive fluid administration in the setting of leaky capillary • syndrome  low threshold for temporary ultrafiltration or dialysis • Avoid over-distension of the lungs in the ventilatory management •  6 to 8 ml/kg tidal volume with ↑ PEEP and ↓ Pmax (≤30 cm H2O) • and higher frequency ventilation with volume assist-control • ventilatory mode ↓risk of volutrauma and barotrauma • Independent lung ventilation if needed 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  23. Treatment Special Considerations Nitric Oxide NO intracellular cGMP production pulmonary vasodilatation maintanence of pulmonary capillary integrity prevention of leukocyte adhesion and platelet aggregation 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  24. Treatment Special Considerations Nitric Oxide ischemie/reperfusion injury ↓NO and ↓cGMP ↑pulmonary vascular ↑ endothelin-1 production resistance (potent vasoconstrictor) ↑ leukocyte adhesion and ↑ platelet aggregation 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  25. 232 papers were reviewed • 6 papers represented the best evidence to answer this question • These are non-randomised and/or uncontrolled studies • There are currently no randomised controlled studies that demonstrate • a reduction in morbidity or mortality • Routine use of prophylactic inhaled NO in lung transplantation • is not recommended 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  26. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Treatment Special Considerations Nitric Oxide • In case of established severe PGD with severe hypoxemia • and/or elevated PAP  NO use is justified • NO might help maintain the patient´s stability and • prevent the need for ECMO or retransplantation 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  27. Treatment Special Considerations Prostaglandins Prostaglandins pulmonary vasodilatation inhibition of platelet aggregation ↓ pro-inflammatory cytokines + ↑ anti-inflammatory cytokines 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  28. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Treatment Special Considerations Prostaglandins • In case of established severe PGD  prostaglandin use • appears to be helpful • Positive effects are shown in several animal studies • Further clinical studies are required 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  29. ISHLT Working Group on Primary Lung Graft Dysfunction J Heart Lung Transplant 2005 Treatment Special Considerations ECMO • Potentially life-saving treatment option for patients with • severe PGD after LuTX • Early (<24 h) institution offers significant survival benefit • ECMO should not be initiated later than 7 days postop •  virtually no survivors within this group • Selected patients with higher risk for developing PGD • may benefit from prophylactic use of ECMO 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  30. Treatment Special Considerations ECMO • PGD without hemodynamical instability  veno-venous • PGD with hemodynamical instability  veno-arterial 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  31. Treatment Special Considerations Re-Transplantation • Re-transplantation may be considered in highly selected • patients with PGD • This sub-group represents a very high-risk population • with a poor survival Aigner C,et al. J Heart Lung Transplant 2008;27:60-5 Strueber M,et al. J Thorac Cardiovasc Surg 2006;132;407-12 Osaki S,et al. Eur J Cardiothorac Surg 2008;34:1191-7 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

  32. Summary • Characteristics: poor oxygenation • pulmonary edema • low pulmonary compliance • infiltrates on CXR • Incidence between 10 to 57% • Associated with poor short-term and long-term outcome after LuTX • Donor-related risk factors: age,trauma,ischemic time,preservation sol. • Recipient-related risk factors: BMI>25, female, SLuTX, PAPs>60,Ind • Treatment: avoid excessive fluid administration • avoid over-inflation in the ventilatory management • NO, prostaglandin, surfactant are promising options • Early use of ECMO is an important option in severe forms • Re-Transplantation should be evaluated very restrictively first hours up to 3 d 15th Annual Congress of Turkish Thoracic Society, 11-15 April 2012

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