Heart-Lung Transplantation

Background

Heart-lung transplantation (cardiopulmonary transplantation) is the simultaneous surgical replacement of the heart and lungs in patients with end-stage cardiac and pulmonary disease. [123This procedure remains a viable therapeutic alternative for patients in specific disease states, though the frequency of application has substantially diminished in recent years. [4]

Causes of end-stage cardiopulmonary failure that necessitate cardiopulmonary transplantation range from congenital cardiac disease to idiopathic causes and include the following:

  • Irreparable congenital cardiac anomalies with pulmonary hypertension (Eisenmenger complex)

  • Primary pulmonary hypertension with irreversible right-heart failure

  • Sarcoidosis involving only the heart and lungs

Early clinical applications of heart-lung transplantation met with poor results secondary to poor patient selection, inexperience with preservation methods, insufficient understanding of pulmonary physiology, and primitive methods of immunosuppression. These early and disappointing clinical results confined the procedure to the laboratory until other areas of transplantation biology advanced.

Discoveries and advancements in cardiac transplantation were eventually applied to heart-lung transplantation, including the development of rabbit antithymocyte globulin to deter rejection and endomyocardial biopsy techniques to detect rejection.

The discovery and application of cyclosporine A was a turning point. With this new immunosuppressive agent, rejection could be controlled with less steroid use. This development addressed the difficulties incurred in healing of the partially devascularized trachea and constituted a critical step in the reduction of postoperative morbidity and mortality. By capitalizing on these significant advances, human heart-lung transplantation reemerged as a therapeutic alternative for end-stage cardiopulmonary disease.

Candidates for heart-lung transplantation are generally younger persons with a fatal disease. The transplantation process offers hope to these persons. However, the shortage of donor organs makes this lifesaving procedure unavailable to many individuals. Both patients and families need strong physician support, availability, and candor when dealing with issues as they arise.

Indications

Heart-lung transplantation is indicated in patients who have end-stage disease of both the heart and the lungs. Patients with complex congenital heart defects that are not amenable to conventional repair and patients with Eisenmenger syndrome (ie, atrioventricular canal defect, transposition of the great vessels, and truncus arteriosus) are considered candidates for the procedure.

Patients with irreversible right-heart failure secondary to pulmonary hypertension may also require total cardiopulmonary replacement. Patients with cystic fibrosis and end-stage bronchiectasis require replacement of both lungs to avoid the complications of allograft contamination. The best treatment for these patients is double-lung transplantation; however, in patients with compromised cardiac function, a heart-lung transplant is indicated.

Contraindications

Age may be considered a relative contraindication. The lower age limit of candidates for heart-lung transplantation is not defined and is limited only by the availability of donors of suitable size. The upper age limit depends on the patient’s physiologic age, rather than the chronologic age. The age of 60 years is the conventional upper limit for most candidates; however, centers with more experience evaluate patients older than 60 years on an individual basis.

Outcomes

More than 3500 heart-lung transplantations (including retransplantations) were reported to the International Society of Heart and Lung Transplantation (ISHLT) between January 1982 and June 2012; between 2003 and 2012, approximately 50-100 such transplantations were reported annually. [4Incidence is approximately equal in males and females.

The 1-year survival rate after a heart-lung transplant is 65%; the 5-year survival rate is 40%. Early mortality is secondary to surgical losses and acute allograft failure. The late attrition is due to obliterative bronchiolitis and rejection. [5]

The ISHLT reports survival rates of 72% at 3 months, 63% at 1 year, 52% at 3 years, 45% at 5 years and 32% at 10 years. In comparison with lung-only transplantation, heart–lung transplantation had a more pronounced early mortality but better long-term survival. Recipients surviving the first year had a median survival of 10.3 years. 

 Periprocedural Care


Patient Education and Consent

A careful medical and psychosocial evaluation of the candidate must be performed according to established and published program criteria. These criteria are discussed with the patient and family before the initiation of the evaluation, and a candid discussion of issues that disqualify a patient from candidacy for transplantation must be addressed at the onset.

A written contract is negotiated between the transplant center and the patient, with the stipulation that noncompliance with the guidelines is grounds for removal from the program. Both patient and physician must agree to these stipulations. Candid and frequent discussions concerning guidelines, issues, and waiting time should take place.

Patients are instructed to monitor temperature, blood pressure, and pulse oximetry after the procedure and to be alert for symptoms of rejection (which are carefully discussed with the physician). At the first signs of an alteration in their usual state of health, they are to call the transplant center. Patients are educated in detail about the immunosuppressive medications, their actions, and adverse effects.

Because heart-lung transplant patients are at risk for infection caused by their immunosuppressed state, behavioral modification must be encouraged to prevent exposure to certain conditions. Instruct patients to avoid crowds and ill individuals to the extent possible. If patients cannot avoid being in crowds, they should wear a mask in this situation, particularly during the first year after transplantation. Because the lungs are particularly susceptible to injury, encourage the patient to avoid chemical sprays, noxious conditions, fires, and smoke. Stress good general hygiene, including rigorous housekeeping and monitoring of heating and air conditioning systems.

Careful dietary and rehabilitation education is provided. Because of the adverse effects of immunosuppressant drugs, patients are generally maintained on a low-sodium, low-cholesterol diet. Although the steroid regimen is tapered quickly, patients tend to gain weight as a result of the therapy. Dietary discipline is therefore required.

Before transplantation, patients are encouraged to maintain as much normal activity as physically possible in order to maintain muscle tone. If tolerated, a posttransplant cardiopulmonary rehabilitation program is implemented.

After transplantation, the rehabilitation program is instituted early to assist the patient in regaining normal functional status and good general health. In a cohort of 50 patients, exercise performance as measured by oxygen consumption was found to increase from year 1 to year 2 following cardiac transplantation and was related to increase in body weight. [6]

For patient education resources, see the Heart Center and the Lung and Airway Center, as well as Heart and Lung Transplant.

Preprocedural Planning

Pulmonologists are consulted to assist with determining the extent of pulmonary disease and the patient’s suitability for heart-lung transplantation. Pulmonologists also help manage patients during the waiting period.

Cardiologists are consulted to help assess the extent of cardiac disease. Right-heart failure may be reversible, in which case a potential heart-lung candidate may be converted into a lung-transplant candidate. Cardiologists also play a key role in evaluating and managing the potential candidate.

Psychiatrists are consulted to determine the patient’s psychosocial fitness to undergo the procedure, as well as to provide rigorous posttransplant follow-up care. Psychiatric assistance is also invaluable in addressing issues of chronic terminal illness and patient compliance.

Nephrologists are consulted to assist with renal management of patients in whom low cardiac output may have altered renal function.

Infectious disease specialists are consulted to assist with evaluation and management in accordance with findings obtained during the evaluation period.

Social services providers are consulted to assist with financial issues, medication availability, family stress, and patient adaptation.

Dietitians are consulted to assist with dietary issues and patient compliance.

Preprocedural Evaluation

Patients who are being considered for heart-lung transplantation undergo a rigorous screening process to assess their overall physical and psychological health. Because certain disease states recur in the allograft, patients with such conditions may not be suitable candidates for the procedure.

During the waiting period for a potential candidate, carefully monitor for signs of clinical deterioration. Administer standard therapy for congestive heart failure and pulmonary hypertension. Maintain close contact with the transplant center, ensuring that the consultants are informed about the patient’s ongoing medical and social issues.

In the event of deterioration, the transplant center may allow the patient to be admitted and may upgrade their status on the waiting list. Candidates may sometimes deteriorate to the point where transplantation is no longer an option. Thoroughly discuss these issues with the treating physician, patient, and family.

History and physical examination

A thorough history is obtained, which includes inquiries regarding the following factors:

  • Cardiopulmonary disease history

  • Infectious disease exposure

  • Environmental exposure

  • Genetic history

  • Family history

  • Social history, including a substance-abuse profile

A complete physical examination is performed, with particular attention to signs of concomitant disease processes, including gastrointestinal (GI) disturbances, bleeding, vascular insufficiency, and occult carcinoma. All potential candidates are evaluated by social services specialists in order to ensure access to required medications and initiation of appropriate planning.

Laboratory studies

A hepatitis panel can serve as a screen, provided that the patient does not have active antigenicity. Thoracic transplantation in patients with hepatitis C remains controversial and is generally addressed on a center-t-center basis.

HIV positivity remains a contraindication to transplantation.

Testing for other viruses, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV), is valuable. These tests are used to screen patients for past exposure and currently active disease. Past exposure indicates a risk of reactivity; currently active disease should be treated before transplantation is considered. Recipients who are negative for CMV are generally treated with CMV immune globulin.

Immunizations are administered against any diseases for which vaccines are available (eg, rubella and hepatitis).

Fungal serologic testing and tuberculin (TB) skin testing should be performed, with particular attention to environmental exposure. These tests are used to determine past exposure as a predictor of reactivation. Patients with positive TB results are generally treated before being listed for transplantation.

In males, if prostate-specific antigen (PSA) testing yields positive results, the appropriate workup and therapy are instituted before consideration for transplantation.

In females, Papanicolaou test findings should be negative before listing for transplantation considered. Patients with positive test results should be referred for appropriate evaluation and therapy.

Results from the following tests (except alpha1-antitrypsin) should be within reference ranges, and any abnormalities should be assessed for reversibility:

  • Complete blood count (CBC) with differential

  • Platelet count

  • Prothrombin time (PT)

  • Activated partial thromboplastin time (aPTT)

  • Complete chemistry profile, including liver panel, lipid profile, urinalysis, and tests specific to the pulmonary pathology (eg, alpha1-antitrypsin levels)

Blood typing and screening, panel-reactive antibody (PRA) testing, and tissue typing are used to determine the patient’s immunologic suitability for transplantation and to enable donor matching.

Imaging studies

Computed tomography (CT) of the thorax should be performed to determine the thoracic size for donor matching and to detect disease processes that prohibit transplantation.

Echocardiography and dynamic magnetic resonance imaging (MRI) may be performed to determine the patient’s right ventricular ejection fraction (RVEF). An RVEF greater than 30% may indicate potential cardiac recovery, suggesting that the patient might benefit from pulmonary transplantation alone.

Bilateral mammograms in females should reveal no abnormalities before listing for transplantation. Patients in whom abnormalities are revealed should be referred for appropriate evaluation and therapy.

Posteroanterior and lateral chest radiographs determine the patient’s chest size, which is needed for assessment of donor suitability and is also used as a screening test for other thoracic pathologies that may preclude transplantation.

Cardiac and pulmonary evaluation

Pulmonary function test results, including diffusion capacity of lung for carbon monoxide (DLCO) and maximal venous oxygen consumption (MVO2), are expected to be abnormal. If the forced expiratory volume in 1 second (FEV1) is greater than 1 L and the MVO2 is greater than 15 mL/dL/min, the condition may be treatable by means other than transplantation.

Right- and left-heart catheterization is used to determine whether the disease process is reversible or treatable by other means.

Careful evaluation of the patient’s pulmonary vascular resistance is valuable. A resistance lower than 4 Wood units indicates that the patient may benefit from cardiac transplantation alone.

Biopsy

Biopsies of appropriate areas are necessary if the patient is manifesting systemic disease (eg, sarcoidosis). Biopsy procedures determine the extent and activity of disease. Systemic involvement and active disease may be contraindications to transplantation.

Monitoring and Follow-up

Postoperative endomyocardial biopsies are performed at weekly intervals for 2-4 weeks to assess for cardiac rejection.

Chest radiographs and spirograms are routinely obtained to evaluate for the presence of pulmonary rejection or infection. If either entity is considered possible, bronchoalveolar lavage with transbronchial biopsy is performed to streamline the differential diagnosis and direct therapy. [7]

Routine outpatient follow-up care is arranged at prescheduled intervals to monitor for immunosuppression and rejection and to evaluate overall clinical progress. The follow-up interval is determined by the center and may be as frequent as 3 times a week during the first several weeks after discharge. Visits become less frequent as the patient demonstrates stability with the medication regimens and as allograft acceptance (lack of rejection episodes) occurs.

Long-term follow-up care can vary from every 3 months to yearly, depending on the patient’s condition. Each outpatient visit may include the following:

  • Routine tests – These include biochemical screening (including electrolytes, cholesterol, glucose, and liver functions) and immunosuppressant drug levels

  • Pulse oximetry and spirometry – These are performed at each visit

  • Cardiac evaluations – These are obtained at predetermined intervals and include echocardiography to assess the function of the allograft


Technique


Approach Considerations

The application of heart-lung transplantation is limited by the availability of suitable donors. All potential donors have succumbed to brain death secondary to some form of catastrophic event. The condition necessitates ventilator dependency in order to maintain organ viability. In this situation, the lungs become susceptible to injury because of neurogenic pulmonary edema, fat embolism, infectious processes, and atelectasis. These events, coupled with underlying pulmonary pathology in some potential donors, exclude the use of many organs.Direct major chest trauma also precludes donation.

Because of the lung tissues’ short preservation time (4-6 hours), procurement distances are limited.

Potential heart-lung donors must meet brain-death criteria and be free of cardiopulmonary pathology. Donors who smoked may be acceptable candidates, provided that their pulmonary function is preserved and no evidence of infection or malignancy exists.

Current donor criteria include the following:

  • Age younger than 50 years
  • Clear lung fields on chest radiographs
  • Arterial oxygen tension (P a2) >100 mm Hg on 40% inspired oxygen and >300 mm Hg on a 100% oxygen challenge
  • No evidence of tracheobronchial infection on bronchoscopy
  • Low peak inflation pressures

Once donor criteria are met, the donor and potential recipients are matched according to ABO compatibility and organ size. Size matching has been accomplished by various methods, including measurement of chest circumference, assessment of chest wall dimensions on chest radiographs, and estimation of height- and weight-adjusted lung volumes. Ideally, to avoid postoperative compression atelectasis, the donor organs for heart-lung transplantation should be slightly smaller than those of the recipient.

The final decision regarding the suitability of the donor heart-lung allograft can be made only by direct inspection.

Transplantation of Heart and Lung

A median sternotomy incision is made for initial inspection of the heart and lungs. The heart and lungs are mobilized with minimal handling of the pulmonary tissue. The heart is flushed with cold cardioplegia solution while the lungs are simultaneously flushed with cold modified Collins solution after prostaglandins are administered into the pulmonary artery.

The heart-lung block is then removed and placed into a sterile cold electrolyte solution for transport. Care is taken to occlude the trachea during storage and transport.

The recipient operative procedure is performed by using cardiopulmonary bypass. The heart and lungs are removed, with care taken to preserve the phrenic nerves and to address the bronchial artery circulation so as to prevent postoperative bleeding complications.

Next, the donor heart and lungs are inserted (see the image below). The tracheal anastomosis is performed first. The right atrial anastomosis is performed next, followed by the aortic anastomosis. Care is taken to keep the donor trachea as short as possible because of the limited vascularity of the area.

Operative procedure for heart-lung allograft implaOperative procedure for heart-lung allograft implantation.

In addition to the immunosuppressants required for the transplant procedure itself, medications to treat concomitant conditions, including hypertension and diabetes, are required.

Complications

Rejection

Cardiac rejection is monitored by serial endomyocardial biopsies. However, this is not a satisfactory method of assessing pulmonary rejection, because the 2 types of rejection can occur discordantly. Rejection is considered likely when radiographic changes in the lung fields are present. Examination of the cellular content of the bronchoalveolar lavage fluid is an appropriate surveillance method.

If rejection is suggested but not confirmed, treatment is initiated nevertheless. Treatment consists of steroid pulses (methylprednisolone 500-1000 mg/day for 3-5 days), monoclonal antibody treatment, or polyclonal antibody therapy. Cardiac rejection is treated in a similar fashion.

Implantation response

The implantation response is a transient and reversible deterioration in compliance, gas exchange, and pulmonary vascular resistance. It generally occurs immediately after the operation and persists for as long as 1 week. The etiology of the process is multifactorial, including lymphatic disruption, ischemia-reperfusion injury, denervation, surgical trauma, fluid overload, and inadequate preservation (to name a few).

Improvements in preservation techniques, coupled with judicious postoperative diuresis, lead to improved pulmonary function and resolution of the problem.

Infection

The transplanted lung is extremely susceptible to injury and infection. Early mobilization of the patient and aggressive pulmonary therapy may reduce this postoperative complication. Bacteriologic culture of the donor and recipient trachea may demonstrate potential pathogens and guide appropriate prophylaxis. Diagnosis is confirmed by taking a careful history of the patient’s exposure and by obtaining a bronchoalveolar lavage specimen for culture.

Cytomegalovirus (CMV) infection represents a particular hazard. The infection may be a reactivation of recipient disease caused by the immunosuppression or a de novo infection arising from donor tissue, transfused blood, or other sources. Radiographically, diffuse reticular infiltrates appear in the lung fields. The process proceeds rapidly to respiratory failure and death if aggressive treatment is not initiated. For prophylaxis, patients are generally started on ganciclovir 5 mg/kg/day; for treatment, the same drug and dosage are used.

Late viral, fungal, and bacterial infections can occur, depending on exposure. Vigilance and careful historical documentation of the patient’s activities and exposure often provide valuable clues to the infectious agent and guide therapy. Diagnosis and treatment must be prompt.

Allograft vascular disease and bronchiolitis obliterans

Allograft vascular disease of the coronary arteries of the transplanted heart and obliterative bronchiolitis of the transplanted lung remain the main causes of late graft failure and death. In the coronary arteries, a concentric myointimal hyperplasia develops; in the lungs, squamous metaplasia and fibrous replacement of the bronchioles develop. In both cases, the process is progressive.

The etiology of the process continues to be elusive. Current research indicates that initial ischemia-reperfusion injury of the allograft, coupled with repeated rejection episodes, may play a contributing role. To date, the only available therapy is retransplantation. 

Medication Summary

The goals of pharmacotherapy are to prevent complications, to reduce morbidity, and to reduce the chances for organ rejection.

Immunosuppressants

Class Summary

Transplant recipients are maintained on an immunosuppression regimen that includes 1-3 drugs. The chosen combination depends on the training and experience of the center. Generally, the drugs fall into 3 categories: steroids, antimetabolites, and other immunosuppressants.

Cyclosporine (Neoral, Sandimmune, GENGRAF)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for various organs.

For children and adults, base dosing on ideal body weight. Maintaining appropriate levels of the drug in the bloodstream is crucial to the maintenance of the allograft. Foods can alter the level of the drug and time of administration. Medication must be taken at the same time every day.

Neoral is the capsular form of cyclosporine, available in 25- and 100-mg capsules. Sandimmune is the liquid form. GENGRAF is the branded generic form, available in 25- and 100-mg capsules.

Prednisone

Prednisone is an immunosuppressant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is an oral steroid with approximately 5 times the potency of endogenous steroids. Minimal to no oral prednisone should be given for the first 21 days after transplantation unless rejection occurs.

Methylprednisolone (Medrol, Solu-Medrol, A-Methapred)

Methylprednisolone is an immunosuppressant used to treat autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It is the intravenous (IV) form of prednisone.

Tacrolimus (Prograf)

Tacrolimus suppresses humoral immunity (T-cell activity). It is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine can, but it has severe adverse effects, including renal dysfunction, diabetes, and pancreatitis. Levels are adjusted according to renal function, hepatic function, and adverse effects.

Mycophenolate mofetil (CellCept, Myfortic)

Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thus inhibiting their proliferation. It inhibits antibody production.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity. Antimetabolites are used to block the uptake of vital nutrients needed by the cells. As implied, these drugs affect not only the cells of the immune system but also other cells of the body. The potency of therapy is dose-dependent. Azathioprine is not effective treatment for acute rejection episodes but remains an economical choice for long-term immunosuppression.

Sirolimus (Rapamune)

Sirolimus, also known as rapamycin, is a macrocyclic lactone produced by Streptomyces hygroscopicus. It is a potent immunosuppressant that inhibits T-cell activation and proliferation by a mechanism that is distinct from those employed by all other immunosuppressants. This inhibition suppresses cytokine-driven T-cell proliferation by inhibiting progression from the G1 phase to the S phase in the cell cycle.


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