AUTHOR AND EDITOR INFORMATION

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• Miscellaneous
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INTRODUCTION

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Background

Cardiopulmonary transplantation (heart and lung transplantation) is the simultaneous surgical replacement of the heart and lungs in patients with end-stage cardiac and pulmonary disease. This procedure remains a viable therapeutic alternative for patients in specific disease states, although the frequency of application has substantially diminished in recent years. For more information, visit Medscape's Heart-Lung Transplantation Resource Center.

Historical perspective

In Russia during the 1940s, Demikhov performed experimental heart and lung transplants in subprimate species. These procedures were performed without the benefit of hypothermia or cardiopulmonary bypass. The early experience with the procedure in subprimate species suggested that intact pulmonary innervation was needed to maintain normal respiratory patterns and drive. Complete denervation of the heart-lung block led to a diminished respiratory rate, increased tidal volumes, apneic periods, and death.

Subsequent experiments with primates demonstrated significant variation among species with respect to denervation of the allograft block and established that complete cardiopulmonary denervation was compatible with normal respiratory function and long-term survival in primates but not in lower mammals.

These discoveries led to the first human heart-lung transplant, which was performed by Denton Cooley and his team in 1968 on a 2-month-old infant with a complete atrioventricular canal defect and pulmonary hypertension.¹ This and other early clinical applications of the procedure 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.

In 1972, Castaneda et al performed a series of cardiopulmonary autotransplantation procedures on baboons, demonstrating that both the procedure and autograft denervation were compatible with long-term survival.^{2, 3} Discoveries and advancements in cardiac transplantation over the same time period were 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 in the field. With this new immunosuppressive agent, rejection could be controlled with less steroid use, thus addressing the difficulties incurred in healing of the partially devascularized trachea and constituting a critical step in the reduction of postoperative morbidity and mortality. By capitalizing on these significant advances, human heart-lung transplantation reappeared as a therapeutic alternative for end-stage cardiopulmonary disease.

Pathophysiology

Heart-lung transplantation is indicated in patients who have end-stage disease of both the heart and 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, 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.

Frequency

United States

Between January 2006 and January 2007, 37 heart-lung transplantations were reported to the International Society for Heart and Lung Transplantation.⁴

International

More than 2500 heart-lung transplantations were reported to the International Society of Heart and Lung Transplantation between January 1982 and June 2007.⁴ Between 2003 and 2008, approximately 50-100 such transplantations were reported annually.⁴

Mortality/Morbidity

The 1-year survival rate after heart-lung transplantation is 65%; the 5-year survival rate is 40%.

Sex

Incidence is approximately equal in males and females.

Age

• 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 upon the patient's physiologic rather than chronologic age. Age 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.

CLINICAL

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History

• Patients who are being considered for heart-lung transplantation undergo a rigorous screening process to assess their overall physical and psychological health. 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
• All potential candidates are evaluated by social services specialists in order to ensure access to required medications and initiation of appropriate planning.

Physical

A complete physical examination is performed, with particular attention to signs of concomitant disease processes, including GI disturbances, bleeding, vascular insufficiency, and occult carcinoma.

Causes

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

DIFFERENTIALS

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Other Problems to be Considered

Patients with systemic disease must be carefully evaluated. Since certain disease states recur in the allograft, patients with such conditions may not be suitable candidates for the procedure.

WORKUP

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Lab Studies

• Hepatitis panel
• • If the patient does not have active antigenicity, these tests serve as a screen.
  • Thoracic transplantation remains controversial in the patient who has hepatitis C and is generally addressed on a center-to-center basis.
• HIV screen: HIV positivity remains a contraindication to transplantation.
• Viral screens, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)
• • These tests are used to screen patients for past exposure and currently active disease. Past exposure indicates a risk of reactivity, and currently active disease should be treated before considering transplantation.
  • Recipients who are negative for CMV are generally treated with CMV immune globulin.
  • Immunizations are administered for diseases for which they are available (eg, rubella, hepatitis).
• Fungal serologies and tuberculin (TB) skin testing
• • Pay 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 listing for transplantation.
• Prostate-specific antigen (PSA) in males: If results are positive, the appropriate workup and therapy are instituted before consideration for transplantation.
• Papanicolaou test (Pap smear) in females: Findings should be negative before listing the patient for transplantation. If positive, refer the patient for appropriate evaluation and therapy.
• Results from the following tests should be within reference ranges (excluding alpha1 antitrypsin), and any abnormalities should be assessed for reversibility:
• • CBC count 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 type and screen, panel-reactive antibody (PRA), and tissue typing are used to determine the patient's immunologic suitability for transplantation and to enable donor matching.

Imaging Studies

• Obtain a CT scan of the thorax to determine the thoracic size for donor matching and to detect disease processes that prohibit transplantation.
• Conduct echocardiography and dynamic MRI 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 prior to listing for transplantation. If abnormalities are revealed, refer the patient for appropriate evaluation and therapy.
• Posteroanterior and lateral chest radiographs: This study determines 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.

Other Tests

• 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 a patient has a forced expiratory volume in 1 second (FEV₁) value greater than 1 and an MVO2 greater than 15, the condition may be treated by means other than transplantation.

Procedures

• Cardiopulmonary evaluation
• • 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: Resistance of fewer 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.

TREATMENT

Section 6 of 11  

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Medical Care

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.
• Patient deterioration
• • 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 that transplantation is no longer an option.
  • Thoroughly discuss these issues with the treating physician(s), patient, and family.

Surgical Care

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 the donor's underlying pulmonary pathology, exclude the use of many organs. Direct major chest trauma also precludes donation. Because of the lung tissues' short preservation time (4-6 h), 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 their pulmonary function is preserved and no evidence of infection or malignancy exists.
• Current donor criteria include age younger than 50 years, clear lung fields on chest radiographs, and a PaO₂ value greater than 100 mm Hg on 40% inspired oxygen. A 100% oxygen challenge must yield a PaO₂ value greater than 300 mm Hg.
• No evidence of tracheobronchial infection on bronchoscopy should be evident, and peak inflation pressures should be low.
• 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 chest circumference measurements, chest wall dimensions on chest radiographs, and estimation of height- and weight-adjusted lung volumes. Ideally, the donor organs for heart-lung transplantation should be slightly smaller than those of the recipient in order to avoid postoperative compression atelectasis.
• The final decision regarding the suitability of the donor heart-lung allograft can be made only by direct inspection.
• • 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 using cardiopulmonary bypass.
• • The heart and lungs are removed while carefully preserving the phrenic nerves and addressing bronchial artery circulation in order to prevent postoperative bleeding complications.
  • The donor heart and lungs are inserted; 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.

Consultations

• Pulmonologists are consulted to assist with determining the extent of pulmonary disease and the patient's suitability for 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 and convert a potential heart-lung candidate into a lung-transplant candidate. These consultants also play a key role in evaluating and managing the potential candidate.
• Psychiatrists are consulted to determine the psychosocial fitness of the patient to undergo the procedure and 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.

Diet

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, these patients tend to gain weight because of the therapy. Dietary discipline is therefore required.

Activity

Before transplantation, patients are encouraged to maintain as much normal activity as physically possible in order to maintain muscle tone. If tolerated, a cardiopulmonary rehabilitation program is implemented. After transplantation, the rehabilitation program is instituted early in order to assist the patient in regaining normal functional status and good general health.

MEDICATION

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

Drug Category: Immunosuppressants

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.

FOLLOW-UP

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Further Inpatient Care

• Postoperative endomyocardial biopsies are performed at weekly intervals for 2-4 weeks to assess cardiac rejection.
• Chest radiographs and spirograms are routinely obtained to assess 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.⁵

Further Outpatient Care

• 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 include biochemical screening (including electrolytes, cholesterol, glucose, and liver functions) and immunosuppressant drug levels.
  • Pulse oximetry and spirometry are monitored at each visit.
  • Cardiac evaluations are obtained at predetermined intervals and include echocardiography to assess the function of the allograft.

In/Out Patient Meds

• In addition to immunosuppressants, medications to treat concomitant conditions, including hypertension and diabetes, are ordered.

Deterrence/Prevention

• Because these patients are at risk for infection caused by their immunosuppressed state, behavioral modification must be encouraged to prevent exposure to certain conditions.
• Instruct the patient to wear a mask in crowds, 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.
• Instruct the patient to avoid crowds and individuals who are ill.

Complications

• Rejection
• • Cardiac rejection is monitored by serial endomyocardial biopsies. However, this has proven to be an unsatisfactory method to assess pulmonary rejection because the two 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 nevertheless initiated. Treatment consists of steroid pulses (500-1000 mg of methylprednisolone qd for 3-5 d), monoclonal antibody treatment, or polyclonal antibody therapy. Cardiac rejection is treated in a similar fashion.
• Implantation response
• • This is a transient and reversible deterioration in compliance, gas exchange, and pulmonary vascular resistance. The process generally occurs immediately after surgery and persists for as long as 1 week after operation.
  • The etiology of the process is multifactorial, including lymphatic disruption, ischemia or reperfusion injury, denervation, surgical trauma, fluid overload, and inadequate preservation (to name a few).
  • Improvements in preservation techniques coupled with judicious postoperative diuresis leads 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.
  • CMV infection represents a particular hazard. The infection may be a reactivation of recipient disease caused by the immunosuppression or de novo infection 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. Patients are generally started on ganciclovir (5 mg/kg/d) prophylactically to prevent the problem. The same drug and dosage is used for treatment.
  • Late viral, fungal, and bacterial infections can occur based 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. The coronary arteries develop a progressive concentric myointimal hyperplasia. The lungs develop squamous metaplasia and fibrous replacement of the bronchioles. In both cases, the process is progressive.
  • The etiology of the process continues to be elusive. Current research indicates that initial ischemia or reperfusion injury of the allograft coupled with repeated rejection episodes may contribute to the process.
  • To date, the only available therapy is retransplantation.⁶

Prognosis

• 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.⁷

Patient Education

• Patients are instructed to monitor temperature, blood pressure, and pulse oximetry.
• Symptoms of rejection are carefully discussed.
• At the first signs of an alteration in their usual state of health, patients are instructed to call the transplant center.
• Patients are instructed in detail about the immunosuppressive medications, their actions, and adverse effects.
• Careful dietary and rehabilitation education is provided.
• For excellent patient education resources, visit eMedicine's Heart Center and Lung and Airway Center. Also, see eMedicine's patient education article Heart and Lung Transplant.

MISCELLANEOUS

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Medical/Legal Pitfalls

• 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.

Special Concerns

• Candidates for heart-lung transplantation are generally younger persons with a fatal disease. The transplantation process offers hope to these individuals. 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.

MULTIMEDIA

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Media file 1:  Operative procedure for heart-lung allograft implantation.
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Media type:  Image

REFERENCES

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1. Cooley DA, Bloodwell RD, Hallman GL, et al. Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg. Jul 1969;8(1):30-46. [Medline].
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4. Hertz MI, Aurora P, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant. Sep 2008;27(9):937-42. [Medline].
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6. Belperio JA, Lake K, Tazelaar H, et al. Bronchiolitis obliterans syndrome complicating lung or heart-lung transplantation. Semin Respir Crit Care Med. Oct 2003;24(5):499-530. [Medline].
7. Trulock EP. Lung and heart-lung transplantation: overview of results. Semin Respir Crit Care Med. Oct 2001;22(5):479-88. [Medline].
8. Borel JF. Cyclosporin-A--present experimental status. Transplant Proc. Mar 1981;13(1 Pt 1):344-8. [Medline].
9. Burton CM, Milman N, Carlsen J, et al. The Copenhagen National Lung Transplant Group: survival after single lung, double lung, and heart-lung transplantation. J Heart Lung Transplant. Nov 2005;24(11):1834-43. [Medline].
10. Caves PK, Stinson EB, Billingham M, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients. Experience with a new technique. Ann Thorac Surg. Oct 1973;16(4):325-36. [Medline].
11. Cooper DK. Transplantation of the heart and both lungs. I. Historical review. Thorax. Jul 1969;24(4):383-90. [Medline].
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13. Dew MA, DiMartini AF. Psychological disorders and distress after adult cardiothoracic transplantation. J Cardiovasc Nurs. Sep-Oct 2005;20(5 Suppl):S51-66. [Medline].
14. Grady KL, Lanuza DM. Physical functional outcomes after cardiothoracic transplantation. J Cardiovasc Nurs. Sep-Oct 2005;20(5 Suppl):S43-50. [Medline].
15. Harjula A, Baldwin JC, Starnes VA, et al. Proper donor selection for heart-lung transplantation. The Stanford experience. J Thorac Cardiovasc Surg. Dec 1987;94(6):874-80. [Medline].
16. Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official report--1999. J Heart Lung Transplant. Jul 1999;18(7):611-26. [Medline].
17. Jamieson SW, Burton NA, Bieber CP, et al. Cardiac-allograft survival in primates treated with cyclosporin A. Lancet. Mar 10 1979;1(8115):545. [Medline].
18. Jamieson SW, Stinson EB, Oyer PE, et al. Operative technique for heart-lung transplantation. J Thorac Cardiovasc Surg. Jun 1984;87(6):930-5. [Medline].
19. Lee SH, Rubin LJ. Current treatment strategies for pulmonary arterial hypertension. J Intern Med. Sep 2005;258(3):199-215. [Medline].
20. Longmore DB, Cooper DK, Hall RW, et al. Transplantation of the heart and both lungs. II. Experimental cardiopulmonary transplantation. Thorax. Jul 1969;24(4):391-8. [Medline].
21. Lower RR, Stofer RC, Hurley EJ, Shumway NE. Complete homograft replacement of the heart and both lungs. Surgery. Nov 1961;50:842-5. [Medline].
22. McCarthy PM, Kirby TJ, White RD, et al. Lung and heart-lung transplantation: the state of the art. Cleve Clin J Med. May-Jun 1992;59(3):307-16. [Medline].
23. McCarthy PM, Starnes VA, Theodore J, et al. Improved survival after heart-lung transplantation. J Thorac Cardiovasc Surg. Jan 1990;99(1):54-9; discussion 59-60. [Medline].
24. Nakae S, Webb WR, Theodorides T, Sugg WL. Respiratory function following cardiopulmonary denervation in dog, cat, and monkey. Surg Gynecol Obstet. Dec 1967;125(6):1285-92. [Medline].
25. Patterson GA, Todd TR, Cooper JD, et al. Airway complications after double lung transplantation. Toronto Lung Transplant Group. J Thorac Cardiovasc Surg. Jan 1990;99(1):14-20; discussion 20-1. [Medline].
26. Pinderski LJ, Kirklin JK, McGiffin D, et al. Multi-organ transplantation: is there a protective effect against acute and chronic rejection?. J Heart Lung Transplant. Nov 2005;24(11):1828-33. [Medline].
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Article Last Updated: Nov 5, 2008