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

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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

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Diagnosis

• Open Lung Biopsy: diffuse alveolar damage

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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)

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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

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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

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References

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