Cardiac transplantation has become a useful treatment for a variety of patients with end-stage cardiac failure, offering such patients their only chance for dramatic improvement. The procedure has been used much more often in the past decade. More than 80 per cent of all heart transplants have been performed since 1984 and in 1990 more than 3000 were performed worldwide.

Pioneering work in cardiac transplantation was undertaken by Carrel and Guthrie in the early 1900s. In their heterotopic canine cardiac transplant model, a transplanted heart beat for approximately 2 h. The Soviet surgeon Demikhov, working in the 1950s, successfully performed ‘heterotopic’ canine cardiac transplants in which the donor heart was placed intrathoracically without removal of the native heart; he demonstrated the donor heart's ability to support the recipient by exclusion of the native heart from the circulation. Further advances followed the perfection of cardiopulmonary bypass techniques. The first successful long-term experimental ‘orthotopic’ cardiac transplants (in which the native heart is excised and replaced by the donor heart) were performed by Lower and Shumway in 1960; five of eight dogs survived for 6 to 21 days. They emphasized the need for excision of donor and recipient hearts at mid-atrial level, safe cardiopulmonary bypass, and topical hypothermia for cardiac preservation during excision and implantation. The first clinical cardiac transplant was performed in 1964 when Hardy and associates transplanted the heart of a chimpanzee into a human recipient, who lived for several hours. The first successful human to human orthotopic cardiac transplant was performed by Barnard in December, 1967 using techniques derived from laboratory work at Stanford University. The first cardiac transplant at Stanford was carried out 1 month later. Barnard's operation was sensational, widely publicized, and led to many other attempts. However, the results of many additional cardiac transplants performed in 1968 were dismal. Enthusiasm for the operation abated and in 1970 only 20 transplants were performed. Through persistent efforts in the 1970s, largely at Stanford University, improvements in recipient and donor selection, surgical technique, diagnosis of rejection, and postoperative care were achieved. A dramatic improvement in survival rates followed development of techniques for distant graft procurement in the mid-1970s and the introduction of the immunosuppressant cyclosporin in 1980. Presently, in excess of 3000 cardiac transplants are performed worldwide each year demonstrating the procedure's remarkable resurgence and success.

Appropriate recipient selection is critical for optimal results. Recipients should have end-stage heart disease and a life expectancy of 6 to 12 months (i.e. New York Heart Association Class III or IV). All modes of conventional medical and surgical management should have been exhausted. Recipients are usually less than 60 years of age and without other irreversible systemic illness or organ dysfunction, not including prerenal azotaemia or passive hepatic congestion which are considered reversible. There should be no evidence of infection. All recipients should be emotionally stable, with a realistic attitude towards their illness, and must be able to comply with a rigid postoperative protocol requiring daily immunosuppressive medications for the remainder of their lives. These selection criteria were developed to identify the patient population most likely to survive and do well, given the limited supply of donor organs.

Relative contraindications include recent pulmonary infarction, insulin-dependent diabetes mellitus, and age 60 to 70. Recent pulmonary infarction is associated with an increased risk of haemorrhage during the systemic anticoagulation which is necessary for cardiopulmonary bypass. Insulin-dependent diabetes mellitus had been considered to increase morbidity, because an exacerbation of diabetes was expected with immunosuppressant steroids. However, recent reports indicate that cardiac transplantation can be successful in diabetics, although postoperative rejection episodes are more frequent. Although patients older than 60 have not traditionally been considered ideal recipients, cardiac transplantation is now being performed successfully in the 60- to 70-year-old age group.

Preoperative assessment of pulmonary vascular resistance is essential, since elevation increases perioperative mortality. The pulmonary vascular resistance is calculated during right heart catheterization (mean pulmonary artery pressure minus pulmonary capillary wedge pressure divided by the cardiac output in l/min) and should be less than 8 Wood units, as donor right ventricles are unable to function properly against higher pulmonary vascular resistance. During right heart catheterization, pulmonary vasodilators such as nitroprusside or prostaglandin E&sub1; may be administered in attempts to decrease the pulmonary vascular resistance. If resistance falls to less than 8 Wood units with such vasodilators, cardiac transplantation can be performed with acceptable mortality if similar vasodilators are administered in the postoperative period. Nevertheless, early and late mortality is increased; a 1 month mortality of 15 per cent and a 3 month mortality of approximately 50 per cent can be expected if baseline pulmonary vascular resistance is greater than 8 Wood units.

Idiopathic cardiomyopathy is currently the most common indication for cardiac transplantation and accounts for almost 50 per cent of the heart transplants performed yearly. Ischaemic coronary artery disease accounts for another 40 per cent of transplants. Less frequently, recipients suffer from valvular cardiac disease, congenital cardiac disease, or myocarditis. Approximately 3 per cent of transplants are repeat procedures performed for graft atherosclerosis. Much less common indications for cardiac transplantation include doxorubicin-induced cardiotoxicity, amyloidosis, Chagas' disease, cardiac tumours, and refractory arrhythmias.

Optimal results depend on proper donor selection. Appropriate donors are usually less than 45 years of age, have been certified brain dead by an appropriate physician under local laws, have not undergone prolonged cardiopulmonary resuscitation, and have normal electrocardiograms. Screening for communicable diseases such as HIV and hepatitis is performed routinely. No blood-borne infection should be present, although many donors have evidence of pulmonary bacterial colonization. If the status of the donor heart is questionable, further evaluation with central venous pressure monitoring, echocardiogram, or even coronary angiography may be necessary. If the potential donor suffered significant chest trauma, cardiac enzyme levels should be within normal limits.

Potential donors should not be less than 25 per cent of the recipient's weight. Relatively small donors are of greater concern when the pulmonary vascular resistance is elevated and larger donors should be sought since only more muscular hearts will be able to beat sufficiently strongly against the elevated resistance of the pulmonary bed. Care should also be taken when transplanting hearts from female donors into male recipients, as this has been associated with increased mortality.

Donors and recipients should be ABO blood group compatible. If a preoperative cyotoxic antibody screen using 50 to 100 random donor lymphocytes reveals more than 10 per cent to be cross-reactive, a preoperative lymphocyte cross-match is desirable. HLA matching is useful for research purposes. Retrospective analyses of grafts matched at the HLA-A and -B loci show slightly improved long-term survival and fewer infections, but no improvement in rejection rate, likelihood of death from rejection, or length of time to first episode of rejection. Donors and recipients matched for HLA-DR antigens have fewer episodes of rejection and also a slight increase in survival. However, these increases in survival are not sufficient to warrant preoperative HLA matching.

The donor operation is performed through a median sternotomy. If multiple organs are being procured, the chest portion of the operation is performed first or simultaneously with abdominal procedures. After the pericardium is opened, the heart is inspected for contusions or haematomas and is palpated to ensure absence of valvular or coronary artery abnormalities. Aorta, superior vena cava, and inferior vena cava are encircled and controlled. Once the abdominal viscera are dissected, preparations are made to remove all organs. The heart is removed first. Heparin is administered systemically and an ascending aortic cannula is placed for cardioplegia administration. The superior vena cava is ligated and divided. The inferior vena cava and left inferior pulmonary vein are incised, decompressing both ventricular chambers and preventing their distension. The heart is allowed to contract several times and empty completely. An aortic cross-clamp is then placed high on the ascending aorta, just proximal to the innominate artery, and cold crystalloid cardioplegia is infused via the ascending aortic cannula. Preservation is supplemented with topical cold saline. The heart is excised by dividing the aorta just proximal to the aortic cross-clamp; pulmonary veins and pulmonary arteries are divided at the pericardial reflection. The heart is packed in sterile saline at 4°C for transport. Other abdominal organs are subsequently harvested.

The recipient operation is also performed via median sternotomy. Aorta, superior vena cava, and inferior vena cava are encircled and controlled. After systemic heparinization, separate inferior and superior vena cavae cannulae are placed. The aorta is cannulated at the base of the innominate artery and cardiopulmonary bypass is initiated. Once the donor heart has arrived safely, systemic cooling to 26°C is initiated. An aortic cross-clamp and caval snares are applied. The native heart is excised at mid-atrial level. The aorta is divided just above the aortic annulus. The pulmonary artery is similarly divided at the supra-annular level and the native heart is removed. The donor heart is brought on to the operative field and is examined for a patent foramen ovale. The left atrium is opened with incisions connecting the pulmonary vein orifices. Aorta and pulmonary artery are separated. The heart is properly oriented and placed in the recipient's chest cavity. The left atrial anastomosis is performed first, with a running suture. Saline solution at 4°C is infused via an opening in the left atrial appendage and a similar solution is applied to the heart externally. The right atrial anastomosis is completed using running suture, and systemic rewarming is begun. The aortic anastomosis is completed and the cross-clamp is removed. The pulmonary artery anastomosis is completed with the heart beating. The pulmonary artery is decompressed and vented for at least 20 min prior to weaning the patient from cardiopulmonary bypass (allowing reperfusion of the new heart). Resuscitation with pressor support as necessary completes the procedure.

Many immunosuppressant regimens are currently in use, and most centres use at least three agents. Cyclosporin, a fungal metabolite, was introduced clinically in 1980 and is the mainstay of all regimens. Immediately before operation, 2 to 8 mg/kg are administered; a lower dose should be used in patients with renal insufficiency. The drug is continued indefinitely, maintaining a level of 200 to 300 ng/ml as measured by high pressure liquid chromatography. Nephrotoxicity is a common problem and renal function must be closely monitored.

Azathioprine has been used in all forms of transplantation as an antirejection treatment since the early 1960s. Currently, 2 to 5 mg/kg are given preoperatively, followed by a maintenance post-operative dose of 1 to 2 mg/kg.day. The white blood cell count must continuously be monitored: should this decrease or drop below 5000 cells/&mgr;l, the drug must be decreased in dosage or discontinued.

Corticosteroids are the third arm of most cardiac transplant immunosuppressive protocols. Many institutions give 500 mg of intravenous methylprednisolone on completion of the aortic anastomosis, and continue intravenous methylprednisolone for 24 h at a dose of 125 mg every 8 h. After 24 h, oral prednisone is started at a dose of 0.6 mg/kg.day and then tapered slowly over several weeks to a maintenance dose of 10 mg each day. Some institutions have successfully abandoned the use of steroids in maintenance immunosuppression, especially for children, because of their well known side-effects.

‘Induction immunosuppression’ with a fourth agent such as the monoclonal antibody OKT3 is gaining acceptance. Five milligrams of OKT3 are given each day during the initial 2 weeks following transplantation. Such four-drug regimens have decreased the frequency of rejection without increasing the likelihood of infection. No effect on overall survival has been documented.

In the first months following transplantation, rejection and infection are the most common complications: rejection accounts for 30 per cent of all deaths in cardiac transplant recipients and infections for 20 per cent. Seventy per cent of cardiac transplant recipients have an episode of rejection within the first 3 months after transplantation. After 1 year, the incidence of rejection decreases and less than 10 per cent of transplanted patients per year will have rejection episodes. The majority of rejection episodes respond to appropriate treatment. Approximately 50 per cent of recipients have an infection in the first year. The manifestations of severe systemic infection are often subtle, and monitoring for infection as well as for rejection is of paramount importance.

Rejection was difficult to diagnose in the early years, when a variety of criteria were used, including loss of QRS voltage, occurrence of supraventricular arrhythmias, and clinical signs of low cardiac output. The technique of endomyocardial biopsy revolutionized cardiac transplantation, allowing early treatment of rejection and improving survival. In the early postoperative period, endomyocardial biopsies are performed weekly. After 1 to 2 months, the frequency can be decreased. Usually, access to the right ventricular septal biopsy site is via the right internal jugular vein. Under fluoroscopic guidance, a biopsy forceps is manoeuvred to the septal region and at least four samples are obtained for pathological analysis. Right ventricular pressures and cardiac output are measured. Several scales have been developed for grading rejection: those most often used include the ‘Texas system’ and the ‘Stanford system’. A new international grading system has recently been developed and is gaining acceptance (Table 1) 247. The hallmark of rejection-requiring treatment is myocyte necrosis. An infiltrate of lymphocytes is indicative of lesser rejection; myocyte necrosis with extramyocardial haemorrhage is indicative of severe rejection and damage (Fig. 1) 717.

If myocyte necrosis is detected, antirejection therapy should be begun immediately. Initial treatment at most centres is 1g of methylprednisolone intravenously for 3 days. Four days after completion of this ‘steroid pulse’, endomyocardial biopsy is performed to assess treatment results. If significant rejection persists, monoclonal or polyclonal antibodies are administered. If rejection persists despite all treatments and progresses to haemodynamic instability, retransplantation should be considered. Since the introduction of cyclosporin, such refractory rejection has become uncommon.

Diagnosis of infection is difficult since immunosuppression obscures the usual manifestations, and findings are often subtle. Once infection is established, it can progress very rapidly and extremely aggressive, prompt treatment is necessary. An oral temperature over 100.5°F (38°C) must be considered presumptive evidence of infection despite the absence of clinical signs. Such a fever is an indication for thorough culturing, and aggressive evaluation.

Graft atherosclerosis is the most important late complication. It is felt to be a manifestation of chronic rejection based on immunological incompatibility, and manifests primarily as diffuse coronary artery narrowing. The distribution of coronary artery lesions is atypical in that most are distal lesions not amenable to treatment using conventional bypass or angioplasty techniques. Graft atherosclerosis is also atypical in that coronary artery lesions often develop extremely rapidly over several months. An association with cytomegalovirus infection has been documented, but antiviral treatment directed at this agent has not yet been shown to lessen the incidence of graft atherosclerosis. Retransplantation is the only therapeutic option.

Cardiac transplantation is extremely effective for the treatment of end-stage cardiac failure. Survival rates in excess of 90 per cent at 1 year can be anticipated in younger patients with idiopathic or postpartum cardiomyopathies. An overall survival of 81 per cent at 1 year and 69 per cent at 5 years was documented by the registry of the International Society of Heart Transplantation in 1990 (see Fig. 2 718). Cardiac transplantation can no longer be considered experimental and should be offered to all patients who are appropriate candidates.

The first attempts at cardiopulmonary transplantation date to the initial experiments of Carrel and Guthrie with cardiac transplantation. They performed heterotopic cardiopulmonary transplants in rats as early as 1905. Lower and Shumway performed canine cardiopulmonary transplants in conjunction with orthotopic cardiac transplants in the late 1950s and early 1960s. Canine cardiopulmonary transplants were complicated by the fact that dogs, unlike primates, require intact pulmonary innervation for normal respiratory function: subsequent experiments showed that primates could function normally with denervated lungs. The first human heart–lung transplant was performed in 1968 by Cooley in an infant who died after 14 h. With the development of successful cardiac transplantation at Stanford, further experimental work on cardiopulmonary transplantation as a means to circumvent the problem of elevated pulmonary vascular resistance resulted in the first successful clinical heart–lung transplantation programme in 1981. Since that time, cardiopulmonary transplantation has been initiated at many other centres. However, the donor pool for such transplants is small as both a normal heart and nearly perfect lungs are required. Thus, cardiopulmonary transplantation has not yet been as widely applied as cardiac transplantation.

As in cardiac transplantation, appropriate recipient selection is critical. Recipients should be severely limited by their pulmonary and/or cardiac disease with a life expectancy of 6 to 12 months. All modes of conventional medical and surgical management should have been exhausted. However, transplantation of patients with end-stage disease requiring mechanical ventilation has rarely been successful. Generally, recipients should be less than 45 years of age and without other irreversible systemic illnesses or organ dysfunction, not including prerenal azotaemia or passive hepatic congestion which are considered reversible. Many potential recipients, especially those with cystic fibrosis, have evidence of pulmonary bacterial colonization, but there should be no active systemic infection. Mental stability is very important; all patients should be able to comply with a rigid postoperative immunosuppression protocol.

Previous full posterolateral thoracotomy is a contraindication to transplantation; this is associated with excessive bleeding after native heart–lung excision, which is difficult to control after implantation of the graft. More limited thoracotomies or previous open lung biopsy are relative contraindications. Recent pulmonary infarction is also associated with an increased risk of haemorrhage and is a relative contraindication. Insulin-dependent diabetes mellitus is a relative contraindication for the same reasons as in cardiac transplantation.

These criteria allow a substantial population to qualify for cardiopulmonary transplantation. As reported to the International Society for Heart Transplantation in 1991, 33 per cent of heart–lung recipients had primary pulmonary hypertension and Eisenmenger's syndrome accounted for 30 per cent (this includes many patients ineligible for orthotopic cardiac transplant due to combined end-stage left ventricular failure and elevated pulmonary vascular resistance). Cystic fibrosis accounted for 14 per cent of cardiopulmonary transplants and emphysema accounted for 7 per cent.

Criteria for the selection of appropriate donors are similar to those for cardiac transplantation, but, in addition, heart–lung transplant donors must have a Po&sub2; greater than 100 mmHg on 40 per cent inspired oxygen, normal lung compliance with a peak inspiratory pressure less than 30 to 35 mmHg, no major thoracic trauma, and a clear chest radiograph. Any history of smoking should be carefully evaluated. There should be no evidence of pulmonary bacterial colonization on sputum Gram stain or culture. A history of lung disease is unacceptable. These criteria are fairly strict due to problems inherent in pulmonary preservation and severely limit the donor pool. However, such criteria are essential if good clinical results are to be obtained.

Since pulmonary preservation is the limiting factor in cardiopulmonary transplantation, the donor operation assumes paramount importance. Throughout the donor procedure, the lungs must be carefully protected. At no time should inspired oxygen be greater than 40 per cent: if it is necessary to increase inspired oxygen above 40 per cent to maintain a Po&sub2; greater than 100 mmHg, consideration should be given to aborting the transplant. With the advent of multiorgan procurements, good communication between all procurement teams and the anaesthesiologist is essential. As little fluid as possible should be administered intravenously, as the lungs will not be able to clear fluid easily after transplantation. Heart–lung procurement is performed by median sternotomy. The pericardium is opened, the heart inspected and palpated, both anterior pleura incised, and the lungs inspected for contusion or haematoma. The aorta and both vena cavae are encircled and controlled. The main-stem trachea is controlled between the superior vena cava and the ascending aorta. After completion of the abdominal dissection, preparations are made to excise the heart–lung block. After systemic heparinization, a cannula for administration of cardioplegia is placed in the ascending aorta. A cannula is placed in the pulmonary artery for the administration of ‘pulmoplegia’ (modified Collins' solution with magnesium sulphate and dextrose added) after aortic occlusion. For 15 min prior to aortic occlusion, prostaglandin E&sub1; is administered intravenously in a slowly increasing dose from 20 ng/kg.min to 150 ng/kg.min. The superior vena cava is then ligated and divided. The inferior vena cava and left atrial appendage are incised, decompressing both ventricular chambers. The heart is allowed to contract several times and empty completely. The aorta is cross-clamped just below the innominate artery; cold crystalloid cardioplegia is infused through the ascending aortic root cannula and pulmoplegia is administered via the pulmonary artery cannula while gentle lung ventilation is continued, ensuring adequate pulmoplegia distribution. Preservation is supplemented with topical cold saline. The heart–lung block is excised beginning in the posterior mediastinum just anterior to the esophagus. The dissection is carried up the oesophagus from the diaphragm to the main-stem trachea. The aorta is divided just below the cross-clamp. The lungs are inflated to half their total volume and a stapling device placed across the main-stem trachea at least two cartilagenous rings above the carina. The heart–lung block is transported to the recipient at 4°C.

A median sternotomy is used for the recipient operation. Safe removal of the native organs is technically challenging. Great care must be taken to protect phrenic, recurrent laryngeal, and vagus nerves. The aorta is cannulated at the base of the innominate artery; separate inferior and superior vena cavae cannulae are placed. After the donor organs have arrived safely, cardiopulmonary bypass is initiated. Atria are divided at the mid-atrial level, the aorta is divided at the supra-annular level, and the main pulmonary artery is divided. The native heart is removed. Pericardial pedicles preserving the phrenic nerves are created. A 3-cm cuff of pericardium is left anterior to the phrenic nerves, and the posterior incision for the phrenic pedicle is made just anterior to the pericardial reflection of the pulmonary veins. An incision is made in the remaining left atrium to separate the pulmonary veins from the posterior mediastinum. Care must be taken to avoid vagus nerve injury. After division of the left pulmonary ligament, bronchial collaterals to the native lung are divided and the bronchus is transected using a stapling device. The left lung is removed. The right lung is explanted in a similar fashion. At the procedure's conclusion, two pedicles containing the uninjured phrenic nerves remain.

The donor heart–lung block is then prepared for implantation. The tracheal staple line is excised and specimens of donor trachea are obtained for culture. A curvilinear incision is made in the right atrium, avoiding sinoatrial node injury. The recipient trachea is divided two or three rings above the carina in preparation for anastomosis to the donor, which is performed end-to-end using a running polypropylene suture. Right atrial and aortic anastomoses are performed sequentially with running suture, as in orthotopic cardiac transplantation. The new organs are reperfused for 20 to 30 min with the pulmonary artery decompressed and vented. Weaning from cardiopulmonary bypass is performed with resuscitation of the new heart and lungs, using pressors as necessary. Care must be taken to avoid administration of oxygen in excess of 40 per cent as the newly implanted lungs are exquisitely sensitive to oxygen. Early extubation is critical. Surgical interruption of pulmonary lymphatic drainage makes rigorous fluid restriction, early patient mobilization, and meticulous attention to respiratory care essential in the early postoperative period.

Immunosuppressant regimens are similar to those used in cardiac transplantation. However, following the initial dose of methylprednisolone steroids are administered for only 24 h. No further steroids are given for 3 weeks, while tracheal healing progresses. After 3 weeks, oral prednisone, 0.5 mg/kg.day, is begun and slowly tapered to 10 mg/day.

As in other solid organ transplants, cyclosporin is the mainstay of treatment. It is administered prior to operation in a dose of 2 to 8 mg/kg and then continued indefinitely in doses adequate to maintain a level of 200 to 300 ng/ml by high pressure liquid chromotography. Recipients must be monitored closely for nephrotoxicity.

Azathioprine is administered in a fashion similar to that in isolated cardiac transplantation. Some 2 to 5 mg/kg are given preoperatively; maintenance dosing at 1 to 2 mg/kg.day is instituted while the white blood cell count is monitored. During the initial postoperative period most centres administer another agent, such as rabbit antilymphocyte globulin, for additional protection in the period when steroids are not administered. Administration of OKT3 is not advocated because of its association with pulmonary oedema.

Technical complications are more common following cardiopulmonary transplantation than after cardiac transplantation. Operative mortality for heart–lung transplantation is still in excess of 10 per cent, as reported to the International Society for Heart Transplantation in 1991. Thirty per cent of deaths after cardiopulmonary transplantation can be attributed to technical causes, primarily bleeding and phrenic nerve injury. As experience increases, these complications are diminishing.

Rejection and infection are common, as in isolated cardiac transplantation. Twenty per cent of deaths are due to rejection and 30 per cent to infection.

Cardiac and pulmonary rejection may occur simultaneously or asynchronously. Cardiac rejection is less common than in patients undergoing isolated cardiac transplantation, although the reasons for this are unclear. Routine endomyocardial biopsy is, therefore, performed less frequently: usually, one or two endomyocardial biopsies are performed in the first month and subsequently only as clinically indicated. Cardiac rejection is graded using the previously described scales and is treated in the same fashion as isolated cardiac transplants. Pulmonary rejection is difficult to diagnose accurately. Although routine transbronchial endoscopic biopsies are performed at some centres, these have not yet demonstrated the same reliability as endomyocardial biopsies. Other techniques to detect rejection include broncheoalveolar lavage and radionuclide perfusion scanning, neither of which detects rejection reliably. The most reliable indicator of pulmonary rejection currently available is the appearance on chest radiograph, taken in conjunction with clinical suspicion of rejection and pulmonary function testing. If infiltrates develop that are not responsive to antibiotics or antiviral therapies, rejection must be considered and treated presumptively. Despite aggressive treatment of pulmonary rejection, bronchiolitis obliterans, a form of chronic rejection resulting in severely diminished lung function and a pattern of increased interstitial markings on chest radiograph, remains a formidable problem.

As in isolated cardiac transplantation, the diagnosis of infection is made with aggressive evaluation of any fever greater than 100.5°F (38°C) orally. Signs of infection are often subtle and appropriate treatment can only be instituted early if attempts at diagnosis are prompt and thorough.

Combined heart–lung transplant is an effective treatment for primary pulmonary hypertension, Eisenmenger's syndrome, and cystic fibrosis. A survival rate in excess of 70 per cent can be expected at 1 year. Five-year survival data is not yet reliable, but is about 60 per cent.

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