1. Description of the problem
Lung transplantation is an acceptable treatment option for patients with a variety of end-stage pulmonary and cardiopulmonary vascular disorders. While there have been advances in surgical techniques and medical management of lung transplant recipients, complications occurring during the immediate perioperative time period still have great impact on morbidity and mortality following lung transplantation.
Respiratory failure following lung transplantation from a variety of causes, surgical and technical complications, perioperative infections, and acute rejection are the most important early postoperative complications following lung transplantation one may encounter. As in any critical care setting, maintaining adequate oxygenation and perfusion of vital organs is paramount. Prompt recognition of the issues unique to the acutely immunosuppressed lung transplant recipient is important in guiding management.
Primary graft dysfunction (PGD) is a form of acute lung injury resulting in non-cardiogenic pulmonary edema and often significant difficulty in maintaining adequate oxygenation. It is due in large part to ischemia-reperfusion injury from the lung transplant procedure itself and typically manifests within the first 72 hours after transplant as diffuse infiltrates on chest imaging. Histologically, diffuse alveolar damage is seen. PGD is the most important cause of early mortality following lung transplant and has impact on both short- and long-term outcomes following this procedure.
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Surgical complications following lung transplant can potentially involve both bronchial and vascular connections such as acute bronchial anastomotic dehiscence, or pulmonary venous thrombosis or dehiscence. These can be life-threatening and may require a return to the operating room. Additionally, surgical wounds and chest tube sites need to be monitored for bleeding and infections.
Institution of induction immunosuppression results in lung transplant recipients being prone to infections in the perioperative time period, particularly bacterial infections. If prolonged mechanical ventilation is required, concurrent pulmonary infections in addition to PGD can contribute to early respiratory failure. Bloodstream, urinary tract, pleural space, and wound infections can all factor into critical care management and lead to SIRS or sepsis in this population.
Hyperacute rejection (due to blood type incompatibility) is extremely rare, but when manifest, results in profound graft failure shortly after reperfusion. Acute cellular rejection in the allograft during the perioperative time period is possible and can be confused with both PGD and infectious processes. Due to time constraints for allograft viability, direct crossmatching of donor and recipient sera is most often not feasible, leading to the possibility of donor incompatibilities not recognized at the time of transplantation.
Other critical care aspects of the lung transplant patient include:
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Cardiovascular complications – arrhythmias (atrial fibrillation), pulmonary embolism
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Neurologic complications – leukoencephalopathy, cerebral vascular events (gas emboli from incomplete pulmonary vein flushing), lowering of seizure threshold, hyperammonemia
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Renal complications – acute renal failure due to calcineurin inhibitor toxicity, usually reversible
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Other surgical complications – phrenic nerve injury, vagal nerve injury
Clinical features
PGD manifests as impaired oxygenation and allograft infiltrates on chest x-ray, typically within the first 72 hours following lung transplantation. In PGD, PCWP is normal or low, suggesting a non-cardiogenic source of pulmonary edema. PGD is graded similarly to ARDS, with a PaO2/FiO2 ratio of less than 200 with CXR abnormalities signaling the most severe form of PGD, Grade 3. As in ARDS, lung compliance is reduced. On bronchoscopy exam, if any purulence is observed, the amount may be out of proportion to CXR findings, arguing against infection as the main etiology of respiratory failure. PGD may involve the allograft only in a single-lung transplant recipient, but the native lung may have concurrent infiltrates.
Acute bronchial complications postoperatively in the lung transplant patient may manifest as persistent or worsening pneumothoraces, hydropneumothoraces, or increasing subcutaneous air despite functioning chest tubes. Elevated peak airway pressures may also indicate an air leak. Bronchoscopic evaluation is necessary, and CT scanning may delineate air immediately surrounding the anastomosis site(s). Acute pulmonary venous thrombosis may present as respiratory failure and severe radiographic infiltration restricted unilaterally or to one lobe. Acute pulmonary venous dehiscence is potentially catastrophic in presentation and requires emergent surgical exploration to avoid exsanguination.
In the immune-suppressed lung transplant patient, fever may not necessarily herald an underlying infection. Induction therapy often involves administration of corticosteroids, leading to elevation in WBCs; therefore, an elevated WBC count alone cannot be used to determine the presence of active infection. The critical care clinician should have a low threshold for culturing and re-culturing the lung transplant recipient if there is a suspicion for active infection.
Hyperacute rejection presents as diffuse allograft thrombosis and failure in oxygenation and ventilator function. Acute cellular rejection may present more subtly, with non-specific allograft infiltrates, mild effusion, persistent chest tube output, or elevation in the WBC and/or platelet count as a non-specific marker of inflammation.
Key management steps
As with any critically ill patient, maintaining adequate oxygenation and ventilation with perfusion of vital organs is of prime importance. If the lung transplant patient is in the immediate post-operative phase (often still intubated), consideration should be given for placing or maintaining a pulmonary arterial catheter to aid in hemodynamic monitoring. Arterial catheter blood pressure monitoring and accurate measurement of total “in’s and out’s” to assess fluid status is also helpful.
PGD management involves aggressive supportive care. Similar to the treatment of the patient with ARDS, a lung-protective strategy should be employed involving low tidal volumes and avoiding excessive peak airway pressures. PEEP (positive end-expiratory pressure) to help alveolar recruitment and fluid transfer across alveolar membranes can also be used within reason to keep peak inspiratory pressures from being excessive. Overall fluid status should be kept on the dry side with blood pressure support with inotropes and vasopressors used as needed. FiO2 should be weaned to avoid oxygen toxicity. Aggressive sedation and analgesia should be administered to ensure proper interface with the ventilator, and paralytics should be avoided if at all possible.
Enhanced vigilance for concurrent or developing infections is also important, and the critical care clinician should have a low threshold for starting empiric broad-spectrum antibiotic coverage. Additionally, empiric antifungal therapies, particularly in cases of refractory sepsis, should be added when indicated. Antimicrobial coverage should always be tailored as much as possible based on sensitivity data obtained from culture results.
2. Emergency Management
If the postoperative lung transplant patient emergently decompensates, maintaining a functional airway and circulatory support is a priority. Imaging can be obtained rapidly and safely with bedside chest x-ray and a review/update of laboratory values should be performed. Emergent bedside bronchoscopy via endotracheal tube can also be performed when feasible with bronchial alveolar lavage for microbiologic sampling. The most up-to-date hemodynamics from the pulmonary arterial catheter should be reviewed if available. Proper functioning of the ventilator should be confirmed and pulmonary dynamics can be assessed with the assistance of respiratory therapists.
Management points not to be missed
1. Is there a new or worsening chest infiltrate in the allograft?
2. What is the chest tube output? Is there increased bleeding in the pleural space?
3. Is there a suggestion of bleeding on recent blood work?
4. Is there suggestion of developing infection clinically or based on recent blood work?
5. On bronchoscopy, is there evidence of mucous plugging? Are the anastomoses intact? Is there any active bleeding observed?
6. Are there any rhythm disturbances on telemetry?
7. What is the overall fluid status of the patient?
8. Has the patient been maintained on adequate immunosuppression?
3. Diagnosis
Primary graft dysfunction in the postoperative setting in the lung transplant recipient can be assessed by calculating the PaO2/FiO2 ratio and determining if chest x-ray infiltrates are present in the allograft. Severity or grade of PGD is determined using the criteria in Table I.
Table I.
| Grade | PaO2/FiO2 | Radiographic infiltrates consistent with pulmonary edema |
|---|---|---|
| 0 | >300 | Absent |
| 1 | >300 | Present |
| 2 | 200-300 | Present |
| 3 | <200 | Present |
Time points for assessment: T(0 – within 6 hours of reperfusion, 24, 48, and 72 hours)
Other etiologies for impaired oxygenation need to be ruled out, with concurrent infection and heart failure and/or volume overload and being the most common. Bronchoscopy, tracheal aspirate sampling, and hemodynamic measurements can be used to aid in this distinction. In the critically ill patient, there should be a low threshold for culturing other potential sources of infection (blood, urine, wound).
Even in a single-lung transplant recipient, early extubation is possible with normal oxygenation achievable with preferential blood flow to the newly transplanted allograft. Therefore, suboptimal oxygenation – especially if prolonged – should be investigated and treated in the lung transplant recipient who remains critically ill.
Figure 1 and Figure 2 (POD 0 and 3) show representative CXRs from severe PGD in a bilateral lung transplant recipient.
Figure 1.
Representative CXR from severe PGD in a bilateral lung transplant recipient. POD 0.
Figure 2.
Representative CXR from severe PGD in a bilateral lung transplant recipient. POD 3.
Differential diagnosis
Differential for respiratory failure in the postoperative period following lung transplant:
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PGD
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CHF (congestive heart failure – underlying cardiomyopathy, acute coronary event, unstable arrhythmia)
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Pneumonia (donor-derived infection, recipient colonization, or hospital-acquired)
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Acute airways complication
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Transfusion-related acute lung injury
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Hyperacute or acute allograft rejection
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Acute pulmonary embolism
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Acute hemorrhagic event
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Sepsis
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Hypercapnea (oversedation)
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Phrenic nerve injury
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Restriction from abdominal process (abdominal distention, ileus, bowel obstruction)
Confirmatory tests
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CXR
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Current hemodynamic measurements if available
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Tracheal aspirate via endotracheal tube or bronchoalveolar lavage via bronchoscopy
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Ventilator mechanics (compliance, peak airway pressures)
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Pan-culture
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Accurate input/output measurements
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CT scan chest/abdomen/pelvis if stable and further diagnostic information required: assessment of peri-anastomotic air, pleural effusions, infectious source
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Transesophageal echocardiography to evaluate pulmonary vasculature for stenosis or thrombosis
4. Specific Treatment
First-line therapy for refractory hypoxemia from PGD is aggressive supportive therapy. While not proven to be efficacious, most practitioners advocate a lung-protective strategy of ventilation for patients with severe PGD similar to that used in ARDS cases. Because of increased pulmonary capillary leak from lung injury resulting from PGD, avoidance of excessive volume overload is important, and if needed, blood pressure support with inotropes and vasopressors should be administered. Renal replacement therapy (CRRT) may be helpful in managing overall volume status.
Inhaled nitric oxide has theoretical beneficial effects on pulmonary vasodilation, capillary integrity, prevention of leukocyte adhesion and platelet aggregation. Its use has been investigated as a potential prophylactic measure to reduce the incidence of PGD. However, results are mixed and its use to prevent PGD cannot be advocated. However, in cases of established severe PGD, inhaled nitric oxide has been shown in some studies to improve outcomes. Similarly, the use of inhaled prostacyclin has been adopted for its vasodilatory effects, particularly in the setting of delayed right heart recovery in cases of severe pulmonary hypertension.
Drugs and dosages
Inhaled nitric oxide – titrated to effect, up to 40 ppm
Inhaled prostacyclin (epoprostenol) – 20,000 ng/ml
Refractory cases
Early institution of ECMO (extra-corporeal membrane oxygenation) can be considered in refractory PGD cases. ECMO can be a life-salvaging therapy, but only if started within 7 days of transplant. Institution of ECMO requires surgical venous/arterial access and carries risks of thrombosis, vascular complications, and stroke.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Cases of respiratory failure from severe PGD following lung transplantation can lead to prolonged ventilator dependency, on the order of weeks to months, especially if concurrent complications such as infection prolong or prevent recovery. Milder forms of PGD may show steady improvement in oxygenation parameters as well as improved lung compliance. CXR infiltrates may improve, but it is common for residual infiltrates to remain and lag behind clinical improvement.
Short-term survival following adult lung transplantation in the modern era is still good (on the order of 90% at 3 months).
Prognosis
following PGD therefore depends largely on severity, with mild PGD patients having similar prognosis as those patients with no PGD following lung transplantation.
Untreated infection
Acquisition of data to suggest untreated infection or a resistant organism may indicate that infection is the predominant factor in causing respiratory failure. Additionally, bronchoscopy may show significant or worsening purulence to suggest pneumonia. However, in the immunosuppressed lung transplant recipient, causes of respiratory failure and critical illness are very often multifactorial.
Follow-up
Close and continued monitoring is vital in the critical care setting for the lung transplant recipient. Continuous pulse oximetry, arterial blood pressure monitoring, and hemodynamics using pulmonary arterial catheterization are needed for optimal management. Following recovery from an acute critical illness, the lung transplant recipient warrants continued monitoring by specialists familiar with the care of the lung transplant recipient (pulmonologists, infectious disease specialists, endocrinologists, nephrologists, gastroenterologists), and a strong multidisciplinary team that will help with recuperation and recovery (nutrition, physical therapy, respiratory therapy).
Pathophysiology
The pathogenesis of PGD is multifactorial and involves all aspects of the lung transplant procedure, from changes in the donor homeostasis related to brain death, hypothermic organ preservation during transit, and reperfusion of the organ in the operating room upon transplantation. Ischemia reperfusion injury is key to this process that results in lung injury that manifests clinically as impaired oxygenation and non-cardiogenic pulmonary edema and lung infiltrates on CXR.
An inflammatory cascade initiated from donor-derived alveolar macrophages perpetuated via the recipient immune system propagates this injury pattern in the allograft, involving the complement cascade, clotting factors, and several chemokines and cytokines.
Epidemiology
In a series of 80 consecutive lung transplants performed at a single center, respiratory failure in the postoperative period from any cause was seen in 55% of patients, with a mortality rate of 45%. Ischemia-reperfusion was thought to be the cause of the majority of these cases of respiratory failure. PGD occurs in 10% to 25% of all lung transplants performed and is the leading cause of early morbidity and mortality, with 30-day mortality rates of 50%, or 8 times expected in severe PGD cases. Previous definitions of PGD have resulted in variable incidences and mortality rates. However, in 2005, an International Society for Heart and Lung Transplant (ISHLT) consensus statement on PGD was published, aiming to standardize the definition of PGD for research and clinical purposes. Since then, this definition has been validated, with patients experiencing the most severe form of PGD (Grade 3) having the highest mortality rates.
Prognosis
The immediate care in the intensive care unit of the lung transplant recipient can be extremely challenging. This is a situation in which a patient with end-stage lung disease undergoes a complex surgical procedure and is subjected to intense immunosuppression to prevent allograft rejection, increasing risk for infection. The transplantation procedure itself predisposes the patient to experience a form of potentially severe lung injury that has a profound impact on short-term outcomes. Since a more uniform definition of PGD has been established, the impact of severe PGD is clear: hospital length of stay is increased, duration of mechanical ventilation required is prolonged, and functional outcome in survivors of PGD is decreased. Increasing evidence points to the impact PGD has on longer-term outcomes in lung transplant recipients. PGD has been associated with an increased risk for the development of chronic rejection that is directly related to the severity of PGD experienced and independent of acute rejection episodes, bronchiolitis, and community-acquired respiratory viral infections (three widely accepted risk factors for chronic rejection).
Special considerations for nursing and allied health professionals.
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What's the evidence?
Single-center study examining reasons for MICU admission for lung transplant recipients in both early and later time periods after surgery.
Retrospective single-center study examining reasons for respiratory faillure following lung transplantation.
General overview of respiratory failure following lung transplantation.
Comprehensive review of airway complications following lung transplantation.
Overview of postoperative management of the lung transplant recipient from a critical care nursing perspective.
General review of critical care management of the lung transplant donor and recipient.
Comprehensive overview of immediate and chronic medical complications following lung transplantation.
General reviews of PGD.
Comprehensive review of ischemia-reperfusion injury.
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