Primary Graft Dysfunction in Lung Transplantation

Primary Graft DysfunctionPrimary Graft Dysfunctioninin

Lung Transplantation Lung Transplantation

Dr. Ömer Dr. Ömer ŞŞenbaklavacenbaklavacıı

Department of Thoracic and Cardiovascular Surgery Department of Thoracic and Cardiovascular Surgery

University Hospital University Hospital Johannes Gutenberg-University MainzJohannes Gutenberg-University Mainz

1515thth Annual Congress of Turkish Thoracic Society, 11-15 April 2012 Annual Congress of Turkish Thoracic Society, 11-15 April 2012


•Primary Graft FailurePrimary Graft Failure•Early Graft DysfunctionEarly Graft Dysfunction•Reperfusion EdemaReperfusion Edema•Reperfusion InjuryReperfusion Injury•Re-implantation ResponseRe-implantation Response•Re-implantation EdemaRe-implantation Edema

Primary Graft DysfunctionPrimary Graft Dysfunction( PGD )( PGD )


Ischemia/Reperfusion InjuryIschemia/Reperfusion Injury


•First hours up to 3 days after LuTXFirst hours up to 3 days after LuTX•Poor oxygenationPoor oxygenation•Low pulmonary complianceLow pulmonary compliance•Interstitial / alveolar edemaInterstitial / alveolar edema•Infiltrates on chest x-rayInfiltrates on chest x-ray•Diffuse alveolar damage on pathologyDiffuse alveolar damage on pathology

PGDPGDCharacteristicsCharacteristics

ISHLT Working Group on Primary Lung Graft DysfunctionISHLT Working Group on Primary Lung Graft DysfunctionJ Heart Lung Transplant 2005J Heart Lung Transplant 2005


United Network for Organ Sharing / United Network for Organ Sharing / ISHLT RegistryISHLT Registry

Between 1994 and 2002Between 1994 and 2002n = 6984 patientsn = 6984 patients

Incidence of PGD = 10.7 % Incidence of PGD = 10.7 % (literature 10 to 57 %)(literature 10 to 57 %)

30 day-mortality: Patients with PGD = 34.9 %30 day-mortality: Patients with PGD = 34.9 %Patients without PGD = 6.6 %Patients without PGD = 6.6 %

p<0.0001p<0.0001


n=5262 patientsn=5262 patients



Recommendations for Grading of PGD SeverityRecommendations for Grading of PGD Severity

GradeGrade PaOPaO22/FiO/FiO22 Radiographic infiltratesRadiographic infiltrates

00 >300 >300 AbsentAbsent 11 >300 >300 PresentPresent 22 200-300200-300 PresentPresent 33 <200 <200 PresentPresent

T0, T24, T48 and T72T0, T24, T48 and T72 e.g. T72 Grade 3 PGDe.g. T72 Grade 3 PGD



Exclusion FactorsExclusion Factors

Beyond 48 hours following etiologiesBeyond 48 hours following etiologiesshould be taken into accountshould be taken into account

•Hyperacute rejectionHyperacute rejection•Venous anastomotic obstructionVenous anastomotic obstruction•Cardiogenic pulmonary edemaCardiogenic pulmonary edema•PneumoniaPneumonia


•Donor-related risk factorsDonor-related risk factors

•Recipient-related risk factorsRecipient-related risk factors

PGDPGDRisk FactorsRisk Factors



UNOS/ISHLT Registry (6984 Patients)UNOS/ISHLT Registry (6984 Patients)Kuntz CL,et al. Kuntz CL,et al. Clin TransplantClin Transplant 2009;23:819-30 2009;23:819-30

Donor-Related Risk FactorsDonor-Related Risk Factors1.1. Inherent donor factorsInherent donor factors

2. Acquired donor factors2. Acquired donor factors

•AgeAge•Underlying lung diseaseUnderlying lung disease•RaceRace•GenderGender•Smoking historySmoking history •Brain deathBrain death

•TraumaTrauma•Prolonged mechanical ventilationProlonged mechanical ventilation•BronchoaspirationBronchoaspiration•PneumoniaPneumonia•Multiple blood transfusionsMultiple blood transfusions•Hemodynamic instabilityHemodynamic instability•Ischemic timeIschemic time•Preservation solutionPreservation solution



Donor-Related Risk FactorsDonor-Related Risk Factors

VariableVariable Adjusted ORAdjusted OR p-valuep-value

Donor age>45 yrDonor age>45 yr 1.831.83 <0.001<0.001

Donor cause of deathDonor cause of deathCVACVA ReferenceReferenceTraumaTrauma 1.301.30 <0.032<0.032

Eurocollins solutionEurocollins solution 1.441.44 0.0010.001

Ischemic timeIschemic time 1.251.25 <0.001<0.001(per hour above 3 h)(per hour above 3 h)




Brain deathBrain deathbrain death brain death neuro-endocrine dysregulation neuro-endocrine dysregulation hemodynamic and inflammatory changes ( hemodynamic and inflammatory changes ( ↑↑ interleukin-8 interleukin-8

+ + ↑↑ neutrophil infiltration ) neutrophil infiltration ) lung injury lung injury

donor head trauma is independent risk factor for PGDdonor head trauma is independent risk factor for PGD(Kuntz CL,et al. (Kuntz CL,et al. Clin TransplantClin Transplant 2009;23:819-830) 2009;23:819-830)

biopsies from cadaveric kidney donors show higher levels of biopsies from cadaveric kidney donors show higher levels of inflammatory cytokines than from living donors inflammatory cytokines than from living donors higher incidence higher incidence

of PGD and acute rejection of PGD and acute rejection (Koo DD,et al. (Koo DD,et al. Kidney IntKidney Int 1999;56:1551-9) 1999;56:1551-9)




Hemodynamic instabilityHemodynamic instability

Low blood pressuresLow blood pressures

hypoxemiahypoxemia

↓↓energy metabolismenergy metabolism

excessive fluid administrationexcessive fluid administration

lung edemalung edema




RecommendationsRecommendations

Methylprednisolon 15 mg/kg after brain-deathMethylprednisolon 15 mg/kg after brain-deathreduction of inflammatory reaction reduction of inflammatory reaction

Fluid restriction with CVP < 10 mm HgFluid restriction with CVP < 10 mm HgDopamine + VasopressinDopamine + Vasopressin




Lung PreservationLung Preservation•Temperature of preservation solution: 4Temperature of preservation solution: 4°C °C (decreases the metabolic rate to 5% of that at 37(decreases the metabolic rate to 5% of that at 37°C°C ) )•Volume of preservation solution: 60 ml/kgVolume of preservation solution: 60 ml/kg•Pressure of preservation solution infusion: 10-15 mmHgPressure of preservation solution infusion: 10-15 mmHg•Ventilation during lung procurementVentilation during lung procurement•Inflation during storage: not more than 50% of total lung capacity toInflation during storage: not more than 50% of total lung capacity to avoid barotraumaavoid barotrauma•Oxygenation: ventilation and inflation with FiO2 0.3-0.5Oxygenation: ventilation and inflation with FiO2 0.3-0.5 •Storage temperature: Storage temperature: 44°C °C •Preservation solution: extracellular type (Perfadex, LPD, Celsior) is Preservation solution: extracellular type (Perfadex, LPD, Celsior) is better than intracellular type (Euro-Collins)better than intracellular type (Euro-Collins) (Thabut G,et al. (Thabut G,et al. Am J Respir Crit Care MedAm J Respir Crit Care Med 2001;164:1204-8) 2001;164:1204-8)


Recipient-Related Risk FactorsRecipient-Related Risk Factors

•BMI > 25 kg/m2BMI > 25 kg/m2•Female genderFemale gender•Single lung transplantSingle lung transplant•PAP systolic > 60 mmHgPAP systolic > 60 mmHg•Indication: primary or secondary pulmonary hypertensionIndication: primary or secondary pulmonary hypertension primary or secondary pulmonary fibrosisprimary or secondary pulmonary fibrosis

•United Network for Organ Sharing/ISHLT RegistryUnited Network for Organ Sharing/ISHLT Registry•Between 1994 and 2002Between 1994 and 2002•n=6984 Patientsn=6984 Patients Kuntz CL,et al. Kuntz CL,et al. Clin TransplantClin Transplant 2009;23:819-30 2009;23:819-30




VariableVariable Adjusted ORAdjusted OR p-valuep-value

Female genderFemale gender 1.411.41 0.0010.001BMIBMI

≤≤1818 ReferenceReference25 to <3025 to <30 1.661.66 0.0050.005≥≥3030 1.751.75 0.0060.006

Systolic PAP (mmHg)Systolic PAP (mmHg) ≤ ≤3030 ReferenceReference >60 to ≤ 90>60 to ≤ 90 2.062.06 0.0010.001>90>90 2.572.57 0.0020.002

Single lung transplantSingle lung transplant 1.441.44 0.0050.005




DiagnosisDiagnosis OROR Adjusted for PASP ORAdjusted for PASP ORn=5564n=5564 n=4026n=4026

COPDCOPD ReferenceReference ReferenceReferencePPHPPH 4.014.01 2.382.38CFCF 1.411.41 1.401.40IPFIPF 1.761.76 1.941.94SPHSPH 4.034.03 2.182.18SPFSPF 1.591.59 2.572.57



Procedure-Related FactorsProcedure-Related Factors

•Re-transplantation: no elevated risk for PGDRe-transplantation: no elevated risk for PGD•Bleeding and transfusion-related lung injury: unclearBleeding and transfusion-related lung injury: unclear•Reperfusion technique: controlled reperfusion for 10 minReperfusion technique: controlled reperfusion for 10 min

•Role of cardiopulmonary bypass: controversialRole of cardiopulmonary bypass: controversial CPB CPB systemic, pro-inflammatory response systemic, pro-inflammatory response activation of cytokines, leukocytes and complement systemactivation of cytokines, leukocytes and complement system


•386 papers were reviewed386 papers were reviewed•14 papers represented the best evidence to answer this question14 papers represented the best evidence to answer this question

6 papers showed significantly worse outcomes with CPB6 papers showed significantly worse outcomes with CPB6 papers showed no difference6 papers showed no difference2 papers showed a mixture of both depending on the specific2 papers showed a mixture of both depending on the specificoutcomes assessedoutcomes assessed


Question to be answered: Question to be answered:

Can elective use of CPB avoid the overperfusion of the first Can elective use of CPB avoid the overperfusion of the first implanted lung thus resulting in decreased incidence of PGD?implanted lung thus resulting in decreased incidence of PGD?

•Sheridan, et al. Sheridan, et al. Ann Thorac SurgAnn Thorac Surg 1998;66:1755-8. 1998;66:1755-8.

•23 DLuTX without CPB23 DLuTX without CPB

•No differences in CXR infiltrate score and quantitative lung perfusionNo differences in CXR infiltrate score and quantitative lung perfusion scan of the initially implanted lung and the second implanted lung.scan of the initially implanted lung and the second implanted lung.



TreatmentTreatmentGeneral ConsiderationsGeneral Considerations

•Avoid excessive fluid administration in the setting of leaky capillaryAvoid excessive fluid administration in the setting of leaky capillary syndrome syndrome low threshold for temporary ultrafiltration or dialysis low threshold for temporary ultrafiltration or dialysis

•Avoid over-distension of the lungs in the ventilatory management Avoid over-distension of the lungs in the ventilatory management 6 to 8 ml/kg tidal volume with 6 to 8 ml/kg tidal volume with ↑ PEEP and ↓ Pmax (≤30 cm H2O)↑ PEEP and ↓ Pmax (≤30 cm H2O) and higher frequency ventilation with volume assist-control and higher frequency ventilation with volume assist-control

ventilatory mode ventilatory mode ↓↓ risk of volutrauma and barotraumarisk of volutrauma and barotrauma

•Independent lung ventilation if neededIndependent lung ventilation if needed


TreatmentTreatmentSpecial ConsiderationsSpecial Considerations

Nitric OxideNitric Oxide

NONO

intracellular cGMP productionintracellular cGMP production

pulmonary vasodilatation pulmonary vasodilatation maintanence of pulmonary maintanence of pulmonary capillary integritycapillary integrity

prevention of leukocyte adhesion and platelet aggregation prevention of leukocyte adhesion and platelet aggregation



Nitric OxideNitric Oxide

ischemie/reperfusion injuryischemie/reperfusion injury

↓↓NO and NO and ↓↓cGMPcGMP

↑ ↑pulmonary vascular pulmonary vascular ↑ ↑ endothelin-1 production endothelin-1 production

resistanceresistance (potent vasoconstrictor) (potent vasoconstrictor)

↑ ↑ leukocyte adhesion and leukocyte adhesion and ↑ ↑ platelet aggregation platelet aggregation


•232 papers were reviewed232 papers were reviewed•6 papers represented the best evidence to answer this question6 papers represented the best evidence to answer this question•These are non-randomised and/or uncontrolled studiesThese are non-randomised and/or uncontrolled studies•There are currently no randomised controlled studies that demonstrateThere are currently no randomised controlled studies that demonstrate a reduction in morbidity or mortalitya reduction in morbidity or mortality•Routine use of prophylactic inhaled NO in lung transplantationRoutine use of prophylactic inhaled NO in lung transplantation is not recommendedis not recommended




Nitric Oxide Nitric Oxide

•In case of established severe PGD with severe hypoxemiaIn case of established severe PGD with severe hypoxemia and/or elevated PAP and/or elevated PAP NO use is justified NO use is justified

•NO might help maintain the patient´s stability and NO might help maintain the patient´s stability and prevent the need for ECMO or retransplantationprevent the need for ECMO or retransplantation



ProstaglandinsProstaglandins

ProstaglandinsProstaglandins

pulmonary vasodilatation pulmonary vasodilatation inhibition of platelet aggregation inhibition of platelet aggregation

↓ ↓ pro-inflammatory cytokines + pro-inflammatory cytokines + ↑ ↑ anti-inflammatory cytokines anti-inflammatory cytokines




Prostaglandins Prostaglandins

•In case of established severe PGD In case of established severe PGD prostaglandin use prostaglandin use appears to be helpfulappears to be helpful

•Positive effects are shown in several animal studiesPositive effects are shown in several animal studies

•Further clinical studies are requiredFurther clinical studies are required




ECMOECMO

•Potentially life-saving treatment option for patients withPotentially life-saving treatment option for patients with severe PGD after LuTXsevere PGD after LuTX•Early (<24 h) institution offers significant survival benefitEarly (<24 h) institution offers significant survival benefit•ECMO should not be initiated later than 7 days postopECMO should not be initiated later than 7 days postop virtually no survivors within this groupvirtually no survivors within this group•Selected patients with higher risk for developing PGDSelected patients with higher risk for developing PGD may benefit from prophylactic use of ECMOmay benefit from prophylactic use of ECMO



ECMOECMO

•PGD without hemodynamical instability PGD without hemodynamical instability veno-venous veno-venous

•PGD with hemodynamical instability PGD with hemodynamical instability veno-arterial veno-arterial



Re-TransplantationRe-Transplantation

•Re-transplantation may be considered in highly selectedRe-transplantation may be considered in highly selected patients with PGDpatients with PGD•This sub-group represents a very high-risk populationThis sub-group represents a very high-risk population with a poor survivalwith a poor survival

Aigner C,et al. Aigner C,et al. J Heart Lung TransplantJ Heart Lung Transplant 2008;27:60-5 2008;27:60-5Strueber M,et al. Strueber M,et al. J Thorac Cardiovasc SurgJ Thorac Cardiovasc Surg 2006;132;407-12 2006;132;407-12Osaki S,et al. Osaki S,et al. Eur J Cardiothorac SurgEur J Cardiothorac Surg 2008;34:1191-7 2008;34:1191-7


SummarySummary

•Characteristics: poor oxygenationCharacteristics: poor oxygenation pulmonary edemapulmonary edema low pulmonary compliancelow pulmonary compliance infiltrates on CXRinfiltrates on CXR•Incidence between 10 to 57%Incidence between 10 to 57%•Associated with poor short-term and long-term outcome after LuTXAssociated with poor short-term and long-term outcome after LuTX•Donor-related risk factors: age,trauma,ischemic time,preservation sol.Donor-related risk factors: age,trauma,ischemic time,preservation sol.•Recipient-related risk factors: BMI>25, female, SLuTX, PAPs>60,IndRecipient-related risk factors: BMI>25, female, SLuTX, PAPs>60,Ind•Treatment: avoid excessive fluid administrationTreatment: avoid excessive fluid administration avoid over-inflation in the ventilatory managementavoid over-inflation in the ventilatory management NO, prostaglandin, surfactant are promising optionsNO, prostaglandin, surfactant are promising options

Early use of ECMO is an important option in severe formsEarly use of ECMO is an important option in severe forms Re-Transplantation should be evaluated very restrictivelyRe-Transplantation should be evaluated very restrictively

first hours up to 3 dfirst hours up to 3 d

Primary Graft Dysfunction in Lung Transplantation

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