Primary Lung Graft Dysfunction

Epidemiology

  • Incidence: occurs in 10-25% of lung transplants

Risk Factors

Donor Risk Factors

  • African-American Race
  • Age <21 y/o and >45 y/o
  • Female Gender
  • Presence of Fat Embolism/Thromboembolism
  • Smoking History

Recipient Risk Factors

  • Elevated FIO2 During Allograft Reperfusion
  • Large-Volume Blood Product Transfusion
  • Overweight Body Habitus/Obesity
  • Preformed Antibodies to Intracellular Antigens (Tubulin, Collagen-V)
  • Preoperative Pulmonary Hypertension
  • Preoperative Sarcoidosis
  • Receipt of Organ from Donor with Any Smoking History
  • Single Lung Transplant
  • Use of Cardiopulmonary Bypass

Physiology

Pre-Transplant Factors

  • Donor Brain Death: leads to altered homeostatic regulation, disordered endocrine function (such as diabetes insipidus), and inflammatory cytokines release
  • Donor Hypotension: may result in acute lung injury
  • Ventilator-Associated Lung Injury in Donor

Retrieval/Cold Storage of the Graft

  • Consequences of Hypothermic Preservation
    • Increased Oxidative Stress
    • Sodium Pump Inactivation: leads to accumulation of intracellular sodium and loss of intracellular potassium
    • Intracellular Calcium Overload
    • Iron Release
    • Cell Death
    • Release of Pro-Inflammatory/Anti-Inflammatory Cytokines

Ischemic-Reperfusion Lung Injury

  • Upregulation of Adhesion Molecules
  • Prothrombic State
  • Release of Pro-Inflammatory Cytokines
  • Release of Alveolar Epithelial Injury Markers
  • Lipid-Mediated Cellular Injury
  • Complement Activation
  • Endothelin Activation
  • Leukocyte Activation

Post-Transplant Factors

  • Aspiration
  • Fluid Overload
  • Hypotension
  • Mechanical Ventilation: especially with high tidal volumes
  • Pneumonia

Diagnosis

  • Open Lung Biopsy: diffuse alveolar damage

Clinical Manifestations

General Comments

  • Onset: within 72 hrs
  • Clinical Grading System (Most Commonly Applied to Bilateral Lung Transplants): calculated on arrival to ICU after transplant and at 24/48/72 hrs
    • Grade 0: pO2/FiO2 >300 + normal chest x-ray
    • Grade 1: pO2/FiO2 >300 + diffuse allograft infiltrates on chest x-ray
    • Grade 2: pO2/FiO2 200-300
    • Grade 3: paO2/FiO2 <200
  • Crucial to Exclude Hyperacute Lung Transplant Rejection (see Hyperacute Lung Transplant Rejection, [[Hyperacute Lung Transplant Rejection]])
    • Pre-transplant panel reactive antibody (PRA) testing should be reviewed: risk of antibody mediated rejection increases with increasing PRA levels (especially with PRA levels >10%)
    • Direct cross match between the donor and recipient should also be performed with flow cytometry

Pulmonary Manifestations

Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])

  • Decreased Pulmonary Compliance
  • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • Intrapulmonary Shunt
  • Increased Pulmonary Vascular Resistance (PVR)

Treatment

Potential Prevention Strategies

  • Limitation of Cold Ischemic Time: preferably <8 hrs
  • Gradual Increase in Perfusion Pressure During Reperfusion
  • Addition of Prostaglandin E1 to Preservation Solution (see Prostaglandin E1, [[Prostaglandin E1]])
  • Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]]): not effective

Management

  • Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]]): improves oxygenation, lowers mean pulmonary artery pressures, and decreases the duration of mechanical ventilation
    • Indications: probably recommended for patients with grade 3 primary graft dysfunction with refractory hypoxemia and pulmonary hypertension
    • Administration: 10-20 ppm
  • Extracorporeal Membrane Oxygenation (ECMO) (see Extracorporeal Membrane Oxygenation, [[Extracorporeal Membrane Oxygenation]])
    • Administration: venovenous is preferred over venoarterial ECMO (due to lower complication rate)
  • Re-Transplantation: generally not recommended

Experimental Therapies to Prevent/Treat Primary Lung Graft Dysfunction

  • Prostaglandins
  • Surfactant Therapty
  • Complement Inhbitors
  • Low Tidal Volume Ventilation
  • Platelet-Activating Factor (PAF) Antagonists
  • Gene Therapy
  • Ischemic Preconditioning
  • Heme Oxygenase Pathway Expression

Prognosis

  • Accounts for Significant Morbidity/Mortality Following Lung Transplant: it represents one of the leading causes of early death after lung transplant
    • 30-Day Mortality: may be as high as 63%
  • Consequences of Primary Graft Dysfunction
    • Longer Duration of Mechanical Ventilation: duration may be as long as 15 days, as compared to 1 day in patients without primary graft dysfunction
    • Longer Hospital Stay
    • Poorer Lung Function Over Time
    • Increased Risk for Development of Chronic Rejection

References

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