Continuing Education Activity

Lung transplantation is the ultimate treatment option for patients with end-stage lung disease. Despite the significant advancement in the medical management of chronic lung diseases like COPD, IPF, cystic fibrosis, etc., lung transplantation remains the best recourse to improve the quality of life. Despite significant technical advancement since its inception in 1983, lung transplantation remains a challenging procedure. Nevertheless, appropriate donor selection, donor organ harvest action, and transport, intraoperative intricacies of the surgical procedure, early postoperative problems of primary graft dysfunction due to ischemia-reperfusion injury, as well as a long-term complication of chronic lung allograft rejection are the details which the treatment providing team should be educated about. This activity highlights the role of the interprofessional team in the management of patients undergoing lung transplantation.

Objectives:

• Describe the intraoperative steps of the lung transplant procedure.
• Identify the indications and contraindications for lung transplantation.
• Summarize the postoperative complications of the lung transplant procedure.

Introduction

Lung transplantation is a well-established life-saving treatment to improve the quality of life of patients with end-stage respiratory failure not responding to other medical or surgical interventions.[1] The 36th adult lung and heart-lung transplant report summarize data from 69,200 adult lung transplants that have been performed through June 30, 2018, and reported to the International Thoracic Organ Transplant Registry.[2] The US Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR) reported survival rates of 85% at 1 year, 68% at 3 years, and 55% at 5 years.[3] 

Because lung transplantation is evolving both in the application and in success, it is worthwhile to be acquainted with the procedure. The first lung transplant procedure was performed by Dr. James Hardy and colleagues at the University of Mississippi in 1963. The recipient had chronic obstructive pulmonary disease (COPD) but was a suboptimal candidate for several reasons, including the presence of advanced lung cancer and renal insufficiency.[4] While the first successful combined heart and lung transplant was performed in 1981. Since then the field of lung transplantation has advanced in the selection of candidates, operative techniques, critical care management, immunosuppression, and long-term follow-up.

Anatomy and Physiology

The lungs are paired organs (right and left). The right and left mainstem bronchus from the respective lung join together at the carina to form the central trachea. Each lung has three surfaces that include the costal, medial, and the inferior or diaphragmatic surface. A serous membrane encloses each lung called pleura, which has two layers; the outer (parietal pleura) and the inner (visceral pleura). The right lung is shorter and wider than the left lung, and the left lung occupies a smaller volume than the right. 

The right lung consists of upper, middle, and lower lobes, whereas the left lung has only upper and lower lobes. The lingula in the left lung is part of the upper lobe. The right lobe is divided by a horizontal (which divides the upper and middle lobe) and the oblique fissure (which divides the middle and lower lobes). In the left lobe, there is only an oblique fissure that divides the upper and lower lobe.

Each lobe of the right and the left lung is made up of several individual structurally ad functionally independent units called the bronchopulmonary segments. There are a total of 18 bronchopulmonary segments; 10 on the right and 8 on the left. Each segment has its own separate artery, segmental bronchus, autonomic nerves, and lymph vessels.

The hilum or root of the lung lies on the medial part where the visceral and parietal pleura meet. The pulmonary vasculature and the bronchi enter and exit from the lung through the hilum. The pulmonary arteries ( right and left) carry deoxygenated blood from the right ventricle to the lungs. The pulmonary veins (4 in number) carry oxygenated blood from the lungs to the left side of the heart. For recipient pneumonectomy, each of these need to be identified, completely dissected, transected, and stapled.

Lung resections can be anatomical like segmentectomy, lobectomy, or pneumonectomy (depending upon the extent of the lung removed) or non-anatomic in the form of wedge resection.

Lungs suitable for transplantation are harvested from brain-dead donors (BDD) or after the declaration of circulatory death (DCD). Traditionally, lungs have been preserved in ice using cold static preservation before transfer to the recipient hospital for transplantation. However, due to the lack of ideal lung donors in the majority of cases and the recent findings that cold static preservation leads to exaggerated ischemia-reperfusion injury, lungs are now being transported in normothermic perfused condition. For this purpose, ex vivo lung perfusion has been recently developed for transport as well as evaluation and reconditioning of the donor's lungs before transplantation.[5]

Indications

The primary indications for a lung transplant are:[6]

Chronic obstructive pulmonary disease (COPD). Timing of listing (presence of one criterion is sufficient):

• BODE index ≥7
• FEV <15% to 20% predicted.
• Three or more severe exacerbations during the preceding year.
• One severe exacerbation with acute hypercapnic respiratory failure

Cystic Fibrosis. Timing of listing:

• Chronic respiratory failure.
• With hypoxia alone (partial pressure of oxygen [PaO] <8 kPa or <60 mm Hg).
• With hypercapnia (partial pressure of carbon dioxide [PaCO2] >6.6 kPa or >50 mm Hg).
• Long-term non-invasive ventilation therapy.
• Pulmonary hypertension.
• Frequent hospitalization.
• Rapid lung function decline.
• World Health Organization Functional Class IV

Interstitial Lung Disease. Timing of listing:

• Decline in FVC ≥10% during 6 months of follow-up (note: a 5% decline is associated with a poorer prognosis and may warrant listing).
• A decline in DLCO ≥15% during 6 months of follow-up.
• Desaturation to <88% or distance <250 m on 6-minute-walk test or >50 m decline in 6-minute-walk distance over a 6-month period.
• Pulmonary hypertension on right heart catheterization or 2-dimensional echocardiography.
• Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation
• Alpha-1-antitrypsin (alpha-1) deficiency

Pulmonary Vascular disease/Idiopathic pulmonary arterial hypertension (IPAH). Timing of transplant listing:

• NYHA Functional Class III or IV despite a trial of at least 3 months of combination therapy including prostanoids
• Cardiac index of <2 liters/min/m2
• Mean right atrial pressure of >15 mm Hg
• 6-minute walk test of <350 m
• Development of significant hemoptysis, pericardial effusion, or signs of progressive right heart failure (renal insufficiency, increasing bilirubin, brain natriuretic peptide, or recurrent ascites)

Bronchiectasis, and Sarcoidosis.

• Other indications include constrictive bronchiolitis, connective tissue diseases, pulmonary hypertension secondary to congenital cardiac conditions, and others.

Contraindications

Absolute contraindications to lung transplantation are as under:

• Recent history of malignancy
• Significant dysfunction of another major organ system (such as the heart, liver, kidney, or brain) refractory to therapy
• Severe atherosclerotic disease with suspected or confirmed end-organ ischemia or dysfunction and/or coronary artery disease, not amenable to revascularization
• Acute medical instability, such as acute sepsis, myocardial infarction, and liver failure
• Uncontrollable bleeding disorder
• Chronic infection with highly virulent and/or multidrug-resistant pathogens,
• active Mycobacterium tuberculosis infection
• Significant chest wall or spinal deformity likely to result in severe restriction after transplant
• Class II or III obesity (BMI ≥ 35 kg/m2),
• Noncompliance with medical therapy,
• Psychiatric or psychologic conditions that may impede the ability to cooperate with the medical and health-care team and/or adhere to complex medical therapy and lack of adequate or reliable social support.

Relative contraindications are

• Age > 65 years and low physiologic reserve
• Class I obesity (BMI ≥ 30 but < 35 kg/m2) particularly central
• Severe malnutrition
• Severe osteoporosis
• Prior extensive chest surgery with lung resection
• Infection with highly resistant or highly virulent pathogens and HIV infection[6]

Personnel

The lung transplant team includes:

• A multidisciplinary team consisting of a pulmonologist, cardiothoracic surgeon, anesthesiologist, surgical assistants and nursing staff, perfusionists, transplant nurse, physical therapist, psychologist, and social worker. 
•  The transplant pulmonologist is responsible for the selection of end-stage lung disease patients that would benefit from lung transplantation as well as appropriate preoperative optimization.
• The Cardiothoracic surgeon- perform the lung transplantation and takes care of the patient in the immediate post-operative period. At times high-risk patients need to be bridged to lung transplant by putting them on an extracorporeal membrane oxygen device.
• The Transplant nurse coordinates various parts of the procedure including workup, patient education, and follow-up
• Additionally, transplantation cardiologists, psychologists, intervention counselors, infectious disease specialists, hematologists, and physical therapists play an important role.

Preparation

 Preparation for lung transplantation includes the following:

• Pre-anesthetic work-up which includes routine blood work, electrocardiogram (ECG), echocardiogram and other radiological and diagnostic procedures, history and physical examination
• Consent for lung transplant surgery
• When a donor is identified, lung allocation follows an established algorithm based initially on donor age (pediatric vs adult) and location of the donor hospital. Donor's lungs are then allocated to candidates with the appropriate blood type and size. In the waitlisted patients, the donor organ is then allocated to the patient with the highest lung allocation score (LAS). The LAS prioritizes patients based on medical urgency and the likelihood of benefiting from the transplant procedure.[7]
• Pre-operatively, the patient is transferred to the Intensive Critical Care Unit (ICC) to prepare for surgery.
• Certain patients with very severe disease are bridged to lung transplant using extracorporeal membrane oxygenation (ECMO).[8]
• Donor lung images and investigations, as well as the cause of death, are reviewed prior to accepting the organs for harvestation.
• At the donor hospital site, the lung is re-evaluated by bronchoscopy, physical examination after opening the chest, and arterial blood gases from all four individual pulmonary veins prior to accepting them for transplantation.

Technique or Treatment

All patients receive general anesthesia through a double-lumen endotracheal tube. A triple lumen central venous `catheter is inserted into the neck. The majority of centers also place femoral vascular access to expedite percutaneous cannulation for initiation of ECMO support. It is important to insert the venous neckline on the left side as post-procedure extracorporeal membrane oxygenation (ECMO) may be needed. A Swan Ganz catheter is also placed to monitor PA pressures. During lung transplantation (LTx), the close interrelation between heart and lung function makes TEE (trans-esophageal echocardiography) an invaluable tool for instantly monitoring the physiopathological situation in the subsequent steps of the intervention.[9]

The patient is placed supine and prepped from neck to knee. For a single lung transplant, anterolateral thoracotomy is used. Bilateral transplants are traditionally done using a clamshell incision with sternal splitting. More recently, a sternal sparing approach has been used whenever possible. Split function testing preoperatively decides which side of the lung is transplanted first, with the severely diseased side transplanted first. The lungs are separated from the chest cavity, dense adhesions due to prior surgeries or pleurodesis can make this step difficult. A traction suture is taken on the dome of the diaphragm and brought out. The pericardium is opened at this point to aid with hilar dissection. Any adhesions are released with electrocautery. The hilar dissection is then carried out.

The diseased lung is removed, beginning with the division of the inferior pulmonary ligament. The pulmonary artery and pulmonary veins (PV) are subsequently divided using an endo stapler taking care to leave behind an adequate stump for anastomosis. Heparin is given systemically to keep the vessels patent. The hilum is prepared by the circumferential opening of the pericardium. The bronchus is prepared centrally. The other team prepares the donor lungs for implantation. The bronchus, pulmonary artery, and veins are prepared to keep the graft on ice. The lungs are then implanted, beginning with the bronchial anastomosis. This anastomosis is performed with a 3-0 prolene running suture in a telescoping fashion. The pulmonary artery is then aligned and anastomosed in an end-to-end fashion using a 4-0 prolene running suture. The pulmonary vein anastomosis is done last, and adequate care is taking to de-air the before tying down the sutures. 

Ventilation after graft implantation is initiated with low FiO2 to avoid reperfusion injury, and gradually the mechanical ventilation is adjusted. The cardiopulmonary bypass for hemodynamic support is used during the operation whenever indicated. It supports the heart and lungs during surgery by providing circulatory support and oxygenation until the allograft functions. Thorough hemostasis is achieved at the end of the procedure. Similarly, the other lung is transplanted in a bilateral transplant procedure.

A the end of the procedure, three chest tubes are inserted: anteriorly in the chest, along the diaphragm, and posterolaterally towards the apex in the chest. The thoracotomy incision is closed in then closed in layers. The pectoral fascia, the subcutaneous layer, the subdermal layer, and the skin are re-approximated. After the transplant, the double-lumen endotracheal tube is exchanged for a single lumen. Bronchoscopy is performed at this time to assess the anastomotic suture line and remove any secretions or clots. Meanwhile, a nasoenteric feeding tube is also placed. Postoperative allograft dysfunction is managed with peripheral venovenous ECMO. The surgical duration is usually six to 10 hours.

Post-operatively, patients are transferred to the critical care unit. Here they remain on a ventilator until they regain consciousness and lung function is appropriate to start weaning. Adequate pain control is provided and anti-rejection drugs right away. It is critical to managing fluid intake, hemodynamics, and optimizing the outcome of end-organ perfusion in the intensive care unit. The majority of recipients receive immunosuppression consisting of steroids, a cell cycle inhibitor, and a calcineurin inhibitor. All patients undergo routine postoperative surveillance bronchoscopy and maintenance immunosuppression. Once stable,  they are shifted to the cardiothoracic nursing unit, based on the recovery. From here begins the post-transplant rehabilitation, which includes physical therapy and breathing and speech exercises. The expected length of stay is one to three weeks for an uncomplicated lung transplant.[10]

Complications

Complications following lung transplantation can be categorized as:

1. Immediate

• Hyperacute rejection
• Donor-recipient mismatch

2. Early

• Bleeding
• Primary graft dysfunction - (as a consequence of ischemia-reperfusion injury) is the most common cause of mortality in the early postoperative period and long-term complications like chronic rejection. PGD grade 3 should be expeditiously treated with ECMO.
• Pleural complications- pleural effusion, hemothorax, pneumothorax, chylothorax, air leak, 
• Acute kidney injury

3. Intermediate

• Acute rejection - it can be classified as acute cellular rejection (ACR), which is T-cell mediated, and antibody-mediated rejection (AMR), which is B-cell mediated.
• Airway complications -  bronchial stenosis or dehiscence, which can be treated with either bronchoscopy or surgical intervention
• Vascular complications - pulmonary vein stenosis or occlusion
• Pulmonary thromboembolism
• Infections - CMV, RSV, bacterial, fungal
• Metabolic - hyperammonemia, diabetes mellitus, cardiovascular disease

4. Late

• Chronic allograft lung rejection (or bronchiolitis obliterans)
• Post-transplant lymphoproliferative disease
• Recurrence of primary disease
• Bronchogenic carcinoma

Clinical Significance

Lung transplantation remains the ultimate treatment for end-stage lung disease. With the increasing number of patients with chronic lung diseases as well as the continuous rise in the patients with long-term sequelae of covid-19 induced lung damage, the donor organ shortage will only get enhanced in the coming years leading to an increasing number of deaths of patients waiting for a lung transplant. Ex vivo lung perfusion remains a promising and developing modality to assess and recondition marginal donor lungs prior to transplantation.

Enhancing Healthcare Team Outcomes

The role of a multidisciplinary team of pulmonologist, cardiothoracic surgeon, anesthesiologist, intensivist, perfusionist, psychologists, social worker, and nurses are indispensable for the success of the program. Appropriate preoperative preparation and optimization of the patient and selecting a suitable donor are of utmost importance. The surgical team requires the necessary skill and experience to perform the technically challenging procedure as well as manage the postoperative complications.

It cannot be overemphasized that a dedicated intensive care team taking care of transplant patients is pivotal for favorable patient outcomes. The nursing staff, respiratory therapists, physiotherapists, dieticians, and lastly, the family members of the patient play a very crucial role in the rehabilitation process. The pharmacist and transplant pulmonologist ensure that the patient is on appropriate formulation and dosage of immunosuppression. In summary, detailed planning and discussion with the interprofessional team are highly recommended to decrease morbidity and improve outcomes.