Lung transplantation

Lung transplantation is a life-saving option for patients with respiratory failure, with a high risk of death despite optimal drug therapy. The most common indications are COPD (chronic obstructive pulmonary disease), idiopathic pulmonary fibrosis, cystic fibrosis, alpha1-antitrypsin deficiency, primary pulmonary hypertension. Less common indications are interstitial lung diseases (eg, sarcoidosis), bronchiectasis, congenital heart disease.

Single or double lung transplantation is used with equal success in most lung diseases without cardiac involvement; the exception is chronic diffuse infections (eg, bronchiectasis), in which double lung transplantation is preferred. Heart-lung transplantation is indicated in Eisenmenger syndrome and any lung disease with severe irreversible ventricular dysfunction; cor corpulmonale is not an indication for such transplantation because the condition often recurs after lung transplantation. Single and double lung transplantation are performed equally often and at least eight times more often than heart-lung transplantation.

Relative contraindications include age (65 years for single lung transplantation, 60 for double lung transplantation, 55 for heart-lung transplantation), active smoking, previous thoracic surgery, and, for some patients with cystic fibrosis and in some medical centers, lung infections caused by resistant strains of Burkholderia cepacia, which significantly increases the risk of death.

Almost all lungs are obtained from brain-dead, cardiac-active cadaveric donors. Less commonly, if the cadaveric donor's organs are not suitable, a living donor fraction is used for transplantation (usually in parent-to-child transplantation). The donor must be under 65 years of age, have never smoked, and have no active lung disease as demonstrated by oxygenation (Pa ₀₂ /Fi ₀₂ > 250-300 mmHg), lung compliance (peak inspiratory pressure < 30 cm H2O at V _T 15 ml/kg and positive expiratory pressure = 5 cm H2O), and a normal macroscopic appearance on bronchoscopy. Donors and recipients must be anatomically (determined by radiographic examination) and/or physiologically (total lung volume).

The timing of referral for transplantation should be determined by factors such as the degree of obstruction (FEV1, forced expiratory volume in 1 second, FEV - forced expiratory volume < 25-30% of predicted in patients with COPD, alpha1-antitrypsin deficiency or cystic fibrosis); Pa < 55 mmHg; Pa c > 50 mmHg; right atrial pressure > 10 mmHg and peak systolic pressure > 50 mmHg for patients with primary pulmonary hypertension; progression of clinical, radiographic and physiological symptoms of the disease.

Lung transplantation still remains one of the least developed areas of modern transplantology. Successful implementation of lung transplantation depends on the correct selection of donor and recipient, early diagnosis of rejection crises, the effectiveness of immunosuppression, and correct anti-infective therapy in the postoperative period.

The development of end-stage lung disease with destruction of the lung parenchyma or vasculature is one of the leading causes of disability and mortality in adult patients. Several transplant options have been developed for the treatment of end-stage lung disease, each with its own theoretical and practical advantages. These include lung transplantation and heart-lung transplantation. The choice of lung transplant procedure is based largely on the consequences of leaving the native lung in situ. For example, single-lung transplantation is not indicated in the presence of infection or severe bullous emphysema present in the contralateral lung. Cross-infection would infect the healthy transplanted lung, and severe bullous disease in the native lung can lead to a large perfusion-ventilation mismatch and mediastinal shift. In such cases, preference is given to transplantation of both lungs. Single-lung transplantation is quite feasible without CPB and is rarely complicated by bleeding. Another advantage of single lung transplantation is that the bronchial anastomosis performed heals with significantly fewer complications compared to the single tracheal anastomosis in double lung transplantation.

Double lung transplantation may lead to better functional outcomes in the treatment of end-stage pulmonary hypertension. Double lung transplantation requires the use of CPB with complete systemic heparinization and extensive mediastinal dissection, both of which dramatically increase the risk of postoperative coagulopathy. Bilateral sequential lung transplantation, recently used in clinical practice, may be an alternative to block transplantation of double lungs, since it combines the advantages of using a bibronchial anastomosis and eliminates the need for CPB.

When diagnosing chronic pulmonary hypertension with right ventricular failure, the method of choice is transplantation of the heart-lung complex. However, if the functional capabilities of the heart are preserved, transplantation of an isolated lung may be optimal for a patient with terminal lung disease.

Anatomical and physiological features of the respiratory system and pathophysiological changes in the terminal stage of parenchymatous lung diseases The terminal stage of parenchymatous lung diseases is restrictive, obstructive or infectious in its etiology. Restrictive lung diseases are characterized by interstitial fibrosis with loss of elasticity and extensibility of the lung. Most fibrotic diseases are idiopathic in nature (of unclear origin), but they can also be caused by inhalation damage or immune processes. Interstitial lung diseases affect blood vessels with subsequent manifestation of pulmonary hypertension. Diseases of this category are functionally manifested by a decrease in lung volumes and diffusion capacity with a preserved airflow rate.

The most common cause of end-stage obstructive lung disease is emphysema caused by smoking, but there are other causes, including asthma and some relatively rare congenital diseases. Among them is alpha1-antitrypsin deficiency associated with severe bullous emphysema. In obstructive diseases, airway resistance is greatly increased, expiratory flow rate is reduced, residual volume is greatly increased, and ventilation-perfusion relationships are disrupted.

Cystic fibrosis and bronchiectasis have infectious etiology of the terminal stage of lung diseases. Cystic fibrosis causes obstruction of the peripheral airways with mucus, chronic bronchitis and bronchiectasis. In addition, the terminal stage of pulmonary vascular diseases can be a consequence of primary pulmonary hypertension, which is a relatively rare disease of unknown etiology and is manifested by an increase in PVR due to muscular hyperplasia of the PA and fibrosis of small-diameter arterioles. Another cause of deformation of the pulmonary arterial bed is congenital heart disease with Eisenmenger syndrome and diffuse arteriovenous malformations.

The main indications for transplantation in the terminal stage of any lung disease are progressive deterioration of tolerance, increased oxygen demand and CO2 retention. Other factors that predetermine transplantation are the emergence of the need for continuous infusion support and the manifestation of physical and social incapacity.

Whether the operation is performed depends on the rate of progression of functional impairment and the ability of the right ventricle to compensate for the progression of pulmonary hypertension. Given the limited availability of donor organs, specific contraindications to lung transplantation include severe malnutrition, neuromuscular disease, or ventilator dependence (because respiratory muscle strength is critical for successful recovery); severe chest wall deformity or pleural disease (complicating surgical procedures and postoperative ventilation); and progression of right ventricular failure or glucocorticoid dependence (because healing of the anastomosed airways is hampered by steroids).

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Lung Transplant: Preoperative Preparation

Preoperative pulmonary function testing and right heart catheterization, ventilation/perfusion relationships, and arterial blood gases are very useful in predicting potential difficulties that may occur during and after induction. For example, decreased expiratory flow rates and abnormal pulmonary air trapping may increase hypoxemia and hypercapnia and lead to hemodynamic instability during mask ventilation and after tracheal intubation. Elevated PAP may indicate the need for CPB because right ventricular failure may develop almost suddenly when single-lung ventilation is initiated or the pulmonary artery is sutured. Even in the absence of pulmonary hypertension, a venovenous bypass device is recommended for these cases because gas exchange is so compromised. Obviously, monitoring of systemic and pulmonary arterial pressure is vital in lung transplantation, although severe dyspnea may make internal jugular vein catheterization difficult before induction.

Single lung transplant

The single lung transplant procedure involves pneumonectomy and implantation of the new lung, as well as mobilization of the omentum on a vascular pedicle for transfer to the bronchi. If the native lungs are equally damaged and there is no evidence of pleural scarring, the left lung is chosen for transplantation for technical reasons: the recipient's right pulmonary veins are less accessible than the left, the left bronchus is longer, and the left hemithrax can more easily accommodate a donor lung that is larger than the recipient's. Most surgeons prefer to have the donor lung collapsed during removal, using bronchial blockers and double-lumen endobronchial tubes for this purpose.

For induction of anesthesia, a rapid intubation technique is used, preference is given to drugs that do not have cardiodepressant and histaminogenic effects (for example, etomidate, vecuronium bromide). The use of dinitrogen oxide is avoided in patients with bullae or increased PVR, as well as in cases where 100% oxygen is necessary to maintain acceptable arterial blood saturation. High-dose opioids, potent IA in combination with long-acting muscle relaxants are successfully used to maintain anesthesia. With the onset of single-lung ventilation, as a rule, sharp disturbances in gas exchange and hemodynamics occur. Methods for improving oxygenation in these conditions include the use of PEEP in the dependent lung, CPAP, or high-frequency ventilation in the independent lung with suturing of the pulmonary artery. If at this point PAP increases sharply, right ventricular failure may develop.

Vasodilators and/or inotropic agents may reduce the workload on the right heart; if they are ineffective, single-lung ventilation should be continued. Similarly, if hemodynamic parameters or systemic arterial saturation deteriorate with pulmonary artery clamping prior to pneumonectomy, it may be necessary to use the cardiopulmonary bypass ventilator.

Once the donor lung is re-perfused, the ischemic period ends, but systemic arterial saturation is usually low until the graft is properly ventilated. At this point, bronchoscopy may be required to remove secretions or blood from the airways to restore graft inflation. Once the bronchial anastomosis is complete, the omentum is moved into the chest on an intact vascular pedicle and wrapped around the bronchial anastomosis. Once the chest is closed, the endobronchial tube is replaced with a standard endotracheal tube.

Double lung transplant

Double lung transplantation is most commonly used in patients with primary pulmonary hypertension or cystic fibrosis. Double lung block transplantation is performed in the supine position and, because both lungs are replaced simultaneously, the use of cardiopulmonary bypass is mandatory. Cardioplegic arrest is used to perform anastomoses of the left atrial stump containing all four pulmonary venous orifices. The airway is interrupted at the level of the trachea, so a standard endotracheal tube is used. Because the systemic arterial supply to the trachea is impaired, it is wrapped in vascularized omentum. Extensive retrocardiac dissection often results in cardiac denervation and postoperative bleeding is difficult to control. Bilateral sequential single lung transplantation has been introduced for the same cohort of patients indicated for double lung block transplantation, but it eliminates the need for CPB and tracheal anastomosis. A relative disadvantage of this operation is that with sequential implantation, the ischemic time of the second lung transplant is significantly prolonged.

Lung transplant procedure

A cold crystalloid preservation solution containing prostaglandins is infused through the pulmonary arteries into the lungs. Donor organs are cooled with ice-cold saline in situ or via a cardiopulmonary bypass and then removed. A prophylactic course of antibiotics is given.

Single lung transplantation requires posterolateral thoracotomy. The native lung is removed, and anastomoses are formed with the corresponding stumps of the bronchi, pulmonary arteries, and pulmonary veins of the donor lung. The bronchial anastomosis requires intussusception (insertion of one end into the other) or wrapping with omentum or pericardium to achieve adequate healing. The advantages are a simpler surgical technique, no need for a heart-lung machine and systemic anticoagulants (usually), accurate selection of size, and suitability of the contralateral lung from the same donor for another recipient. Disadvantages include the possibility of ventilation/perfusion mismatch between the native and transplanted lungs and the possibility of poor healing of a single bronchial anastomosis.

Double lung transplantation requires a sternotomy or anterior transverse thoracotomy; the procedure is similar to two sequential single lung transplants. The main advantage is complete removal of all damaged tissue. The disadvantage is poor healing of the tracheal anastomosis.

Transplantation of the heart-lung complex requires medial sternotomy with a pulmonary-cardiac bypass. Aortic, right atrial and tracheal anastomoses are formed, the tracheal anastomosis is formed immediately above the bifurcation site. The main advantages are improved graft function and more reliable healing of the tracheal anastomosis, since the coronary-bronchial collaterals are located within the heart-lung complex. The disadvantages are the long duration of the operation and the need for an artificial circulation apparatus, precise selection of the size, the use of three donor organs for one patient.

Before reperfusion of the transplanted lung, recipients are often given intravenous methylprednisolone. The usual course of immunosuppressive therapy includes calcineurin inhibitors (cyclosporine or tacrolimus), purine metabolism inhibitors (azathioprine or mycophenolate mofetil), and methylprednisolone. Antithymocyte globulin or OKTZ is given prophylactically for the first two weeks after transplantation. Glucocorticoids may be discontinued to allow normal healing of the bronchial anastomosis; they are replaced by higher doses of other drugs (eg, cyclosporine, azathioprine). Immunosuppressive therapy is continued indefinitely.

Rejection develops in most patients despite immunosuppressive therapy. Symptoms and signs are similar in the hyperacute, acute, and chronic forms and include fever, dyspnea, cough, decreased Sa0 ₂, interstitial infiltrates on radiographs, and a decrease in FEV by more than 10-15%. Hyperacute rejection must be distinguished from early graft dysfunction, which is caused by ischemic injury during the transplant procedure. The diagnosis is confirmed by bronchoscopic transbronchial biopsy, which reveals perivascular lymphocytic infiltration of small vessels. Intravenous glucocorticoids are usually effective. Treatment of recurrent or refractory cases is variable and includes high-dose glucocorticoids, aerosolized cyclosporine, antithymocyte globulin, and RT-β-glucose.

Chronic rejection (after 1 year or more) occurs in less than 50% of patients and takes the form of bronchiolitis obliterans or, less commonly, atherosclerosis. Acute rejection may increase the risk of chronic rejection. Patients with bronchiolitis obliterans present with cough, dyspnea, and decreased FEV, with or without physical or radiographic evidence of airway disease. Pneumonia must be excluded in the differential diagnosis. Diagnosis is by bronchoscopy and biopsy. No treatment is particularly effective, but glucocorticoids, antithymocyte globulin, OCTG, inhaled cyclosporine, and retransplantation may be considered.

The most common surgical complications are poor healing of the tracheal or bronchial anastomoses. Less than 20% of single lung recipients develop bronchial stenosis, which results in dyspnea and airway obstruction; it can be treated with dilation and stent placement. Other surgical complications include hoarseness and diaphragmatic paralysis due to recurrent laryngeal or phrenic nerve injury; gastrointestinal dysmotility due to thoracic vagus nerve injury; and pneumothorax. Some patients develop supraventricular arrhythmias, possibly due to conduction changes caused by pulmonary vein-atrial suturing.

What is the prognosis for lung transplantation?

At 1 year, the survival rate is 70% for patients with living donor transplants and 77% for deceased donor transplants. Overall, the survival rate at 5 years is 45%. The mortality rate is higher in patients with primary pulmonary hypertension, idiopathic pulmonary fibrosis, or sarcoidosis and lower in patients with COPD or alpha1-antitrypsin deficiency. The mortality rate is higher with single-lung transplants than with double-lung transplants. The most common causes of death within 1 month are primary graft failure, ischemia and reperfusion injury, and infections (eg, pneumonia) excluding cytomegalovirus; the most common causes between 1 month and 1 year are infections and after 1 year, bronchiolitis obliterans. Risk factors for death include cytomegalovirus mismatch (donor positive, recipient negative), HLA-DR mismatch, diabetes, and previous need for mechanical ventilation or inotropic support. Recurrence of disease is rare, more common in patients with interstitial lung disease. Exercise tolerance is somewhat limited due to the hyperventilatory response. The 1-year survival rate for heart-lung transplantation is 60% for patients and grafts.

Evaluation of the patient's condition after lung transplantation

Postoperative treatment of patients after isolated lung transplantation includes intensive respiratory support and differential diagnostics between rejection and lung infection, for which transbronchial biopsies performed using a flexible bronchoscope are used. Early respiratory failure may occur due to preservation or reperfusion injuries and is characterized by the presence of a pronounced arterioalveolar oxygen gradient, decreased elasticity of the lung tissue (low pulmonary compliance) and the presence of parenchymatous infiltrates, despite low cardiac filling pressure. In these cases, mechanical ventilation with PEEP is usually used, but given the peculiarities of anastomosis of the newly restored airways, inhalation pressure is maintained at minimal values. Fi02 is also maintained at the lowest values that allow obtaining sufficient blood saturation.

In addition to surgical complications, which may include bleeding, hemo- and pneumothorax, early graft dysfunction, and the need for prolonged mechanical ventilation, lung transplantation carries an extremely high risk of infectious complications. The lung is unique among transplanted visceral organs in that it is directly exposed to the environment. Impaired lymphatic drainage, inadequate ciliated epithelial function, and the presence of a suture line across the airways—these and other factors increase the susceptibility of transplanted lungs to infection. During the first postoperative month, bacteria are the most common cause of pneumonia. After this period, CMV pneumonitis becomes the most common. Episodes of acute rejection after lung transplantation are common and difficult to differentiate from infection based on clinical features alone. This distinction is vital because corticosteroids used to treat rejection may worsen pneumonia and promote generalized systemic sepsis. Bronchoalveolar lavage fluid or sputum samples obtained during bronchoscopy may be useful in diagnosing infectious etiologies. Transbronchial or open lung biopsy is necessary to establish the diagnosis of rejection.

Bleeding is the most common complication after en bloc double lung transplantation, especially in patients with pleural disease or Eisenmenger syndrome with extensive mediastinal vascular collaterals. The phrenic, vagus, and recurrent laryngeal nerves are at great risk during lung transplantation, and their injury complicates the process of weaning mechanical ventilation and restoration of adequate spontaneous breathing. Primary healing usually occurs for most bronchial anastomoses; very rarely, bronchial fistulas lead to stenosis, which can be successfully treated with silicone stents and dilations. In contrast, tracheal anastomotic failures often lead to fatal mediastinitis. Obliterating bronchiolitis, characterized by destruction of small respiratory bronchioles, has been described after heart-lung transplantation.

[ 5 ], [ 6 ]