Chapter 95 Heart and lung transplantation
The first successful cardiac transplantation was performed at Groote Schuur, South Africa in 1967 and was followed by operations in other pioneer cardiac centres worldwide. However, it was not until the introduction of ciclosporin (cyclosporine) in 1979 that consistently improved long-term survival was achieved. To date, more than 70 000 cardiac transplantations have been performed in over 200 centres. Further improvements in immunosuppression therapy, surgical technique, detection and treatment of rejection, and general improvements in anaesthesia and postoperative care contributed to the sustained improvements, especially in centres concentrating experience and expertise above a critical mass. Typical survival figures following cardiac transplantation are in the order of 80% survival at 1 year, 70% after 5 years and 50% at 10 years.
With cardiac and lung transplantation accepted as standard treatment for a range of end-stage cardiopulmonary diseases, a large number of recipients may potentially develop critical illness, unrelated or directly related to their original condition. Around 40% of cardiac transplant recipients are readmitted to hospital within 1 year, at least a third requiring admission to intensive care units (ICUs).1 Many of these patients present to the ICUs of non-transplant centres, especially as the number of centres performing transplantation is apparently falling. Therefore, all critical care practitioners need to be aware of the principles of management of the transplant recipient.
CARDIAC TRANSPLANTATION
The main issue with cardiac transplantation revolves around donor availability (Table 95.1). The numbers of potential recipients who fulfil internationally accepted criteria2 (Table 95.2) vastly outnumber the available donors, so the great majority of patients with severe end-stage heart failure inevitably die before a suitable donor heart becomes available.
Table 95.1 Illustration of the disparity between transplant operations and numbers of patients on the UK transplant registry
| Organ transplanted | UK recent annual total | UK registered potential recipients |
|---|---|---|
| Heart | 50–60 | 90–100 |
| Lung | 50 | 275 |
| Heart and lung | 5 | 20 |
Source: www.uktransplant.org.uk.
Table 95.2 Criteria to select cardiac transplant recipients
|
Exclusion criteria
Transpulmonary gradient (mean PAP – mean PAOP) > 15 mmHg (2.0 kPa) or PVR > 5.0 Wood Units despite standardised reversibility testing with nitrates or inhaled nitric oxide
|
NYHA, New York Heart Association; PAOP, pulmonary artery occlusion pressure (or ‘wedge’ pressure); PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance.
The cardiac equivalent of dialysis, for the maintenance of the potential renal transplant recipient until an organ is available, is simply not feasible. However, there has been progress in the medical and surgical management of severe heart failure, some of which are highly specialised treatments with limited availability and some more routine and commonplace (Table 95.3). The use of inotropic drugs such as β-agonists (e.g. dobutamine), catecholamines (e.g. epinephrine) and phosphodiesterase inhibitors (e.g. milrinone) to support the failing heart and circulation is widely practised, as is the use of intra-aortic balloon pump (IABP) counterpulsation. These treatment options are, of course, highly invasive but may be used as rescue therapy in a patient with severe or end-stage cardiac failure who may be waiting for a transplant but in whom some event such as infection of worsening myocardial ischaemia has resulted in a catastrophic deterioration. The response of the failing heart to β-agonists may be disappointing because of the tendency to β-receptor downregulation from chronic overstimulation. In these cases the phosphodiesterase inhibitor drugs such as milrinone and enoximone may have greater and more sustained potency because of their intracellular site of action.
Table 95.3 Non-transplant or bridge to transplant treatment of severe cardiac failure
| Treatment modality | Notes | Applicability |
|---|---|---|
| Angiotensin-converting enzyme (ACE) inhibitors | Reduce cardiac work and improve output – beware exacerbation of renal failure | Ward setting to establish, then as outpatient |
| β-Blockers5,6 | Improve β-receptor numbers and function | Ward setting to establish, then as outpatient |
| Inotropic support | Rescue therapy – rescue and restabilisation sometimes possible – requires central vascular access | CCU or ICU |
| Intra-aortic balloon pump counterpulsation | Rescue therapy combined with inotropes – may restabilise and thus temporary but invasive | CCU or ICU |
| Antiarrhythmic treatments – implantable defibrillators and advanced pacing, e.g. resynchronisation7 | Where recurrent or severe arrhythmias threaten life or cause general destabilisations | Cardiac centre with facilities for electrophysiology |
| Surgical interventions | Routine (e.g. coronary artery bypass) or complex (e.g. anterior ventricular remodelling, mitral reconstruction where severe mitral regurgitation complicates cardiomyopathy) | Specialised cardiac centre |
| Ventricular assist devices (VAD)8 | Short- and medium-term mechanical support for the failed heart – extremely invasive – usually holding stage or bridge to transplant | Specialised cardiac centre |
| Totally implanted artificial heart9,10 | Longer term version of VAD – ultimately may be instead of transplant | Specialised cardiac centre, then possibly home |
CCU, coronary care unit; ICU, intensive care unit.
Some patients who have been deemed inoperable in conventional terms may still benefit from cardiac surgical interventions, though in the setting of severe chronic cardiac failure the risk of death, serious morbidity and prolonged postoperative critical illness may be considered prohibitive. Sometimes a degree of reversible myocardial ischaemia may be demonstrated by thallium scanning and guide subsequent coronary artery bypass grafting. In some cases, the degree of secondary mitral valve regurgitation caused by dilatation of the left ventricle may become a haemodynamically significant lesion of itself and reconstruction of the mitral valve or remodelling of the left ventricle may prove beneficial. In extreme cases of cardiac decompensation and where other organ functions are maintained (an unusual combination) the use of mechanical assistance4 to support the heart and buy time for a donor heart to become available (‘bridge to transplant’) or to provide support while a severe but temporary process (such as some viral myocarditis episodes) subsides (‘bridge to recovery’) may be undertaken in highly specialised centres. The logical conclusion is to develop permanent mechanical support devices obviating the need for transplantation but this goal appears to be a long way in the future. The cost of such therapy in both financial and human terms has to be considered in the context of general health economics. These episodes are still at best pioneering, extremely invasive, draining on the resources of critical care, blood transfusion and pharmacy, and of limited outcome benefits. On the other hand, it can be argued that earlier use of potent mechanical assistance at a stage that other organs have yet to be irretrievably damaged should be more widely attempted and, by inference, outside the major cardiac specialist centres.
DONORS AND RECIPIENTS
Most countries have seen a progressive gradual decline in the numbers of cardiac transplantations performed as a result of decreasing donor availability. Measures to optimise the donor pool for all solid organ transplants and care of potential donors are discussed elsewhere. Donor selection criteria are summarised in Table 95.4.
Table 95.4 General criteria to select cardiac transplant donors
THE TRANSPLANT PROCEDURE
The anaesthetic and perioperative care of these patients is not materially different from any major cardiac surgery and the important principles are well described in the literature.11–13 However, the coordination of the timing of surgery with the arrival of the donor heart, management of the excised donor graft and the immunosuppression protocol are all crucial factors. Organ preservation after harvesting from the donor is especially important and the main factor appears to be limiting the total ischaemic time to less than 4 hours (6 hours at the extreme). The recipient may have to be called in from home and may have a full stomach. The recipient may be elated or extremely anxious, or both.
PHYSIOLOGY AND PHARMACOLOGY OF THE DENERVATED HEART (Table 95.5)
At surgery, the sinoatrial (SA) node of the recipient is retained but does not activate the grafted heart across the suture line. The donor heart has its own SA node but this is not innervated. It may be possible to discern two discrete P waves on the electrocardiogram (ECG). The donor SA node controls the graft heart rate. In the absence of autonomic innervation, only drugs or manoeuvres that act directly on the heart will have an effect. For example, the Valsalva manoeuvre or carotid sinus massage will not affect heart rate, but drugs such as adrenaline (epinephrine), noradrenaline (norepinephrine) and isoprenaline (isoproterenol) exert a positive inotropic and chronotropic effect and β-adrenergic blockers will depress myocardial function. Quinidine and digoxin will influence conductivity through their direct effects only.
| Drug | Effect on recipient | Mechanism |
|---|---|---|
| Digoxin | Normal increase in contractility; minimal effect on AV node | Direct myocardial effect; denervation |
| Adenosine | Fourfold increase in sinus and AV node blocking effect | Denervation supersensitivity |
| Atropine | None | Denervation |
| Epinephrine | Increased contractility and chronotropy | Denervation supersensitivity |
| Norepinephrine | Increased contractility and chronotropy | Denervation supersensitivity |
| Isoprenaline | Normal chronotropic effect | |
| Glyceryl trinitrate | No reflex tachycardia | Baroreflex disruption |
| Quinidine | No vagolytic effect | Denervation |
| Verapamil | AV block | Direct effect |
| Nifedipine | No reflex tachycardia | Denervation |
| β-Blockers | Increased antagonistic effect | Denervation |
| Pancuronium | No tachycardia | Denervation |
| Neostigmine, succinylcholine | No bradycardia | Denervation |
The denervated heart retains its intrinsic control mechanisms,14 e.g. a normal Frank–Starling response to volume loading, normal conductivity and intact α- and β-adrenergic receptors, possibly with enhanced responsiveness.
Denervation results most importantly in an atypical response to exercise, hypovolaemia and hypotension. Any increase in cardiac output from increased heart rate or contractility depends on an increasing venous return and circulating catecholamines, and the response may be delayed. During exercise, muscle contraction increases venous return and the increased circulating catecholamines increase the heart rate. This is a gradual response and, as exercise ceases, the heart rate and cardiac output slowly fall as the catecholamine and the response levels decrease.15 In pathological states, the transplanted heart is especially dependent on adequate filling volumes, and attention to preload is critical.
POSTOPERATIVE CARE
The transplanted heart may have suffered from ischaemic damage before successful reperfusion in the recipient and may require inotropic, chronotropic or even temporary mechanical support. The severity of recipient pulmonary vascular disease may have been underestimated and even modest elevations of pulmonary vascular resistance combined with a degree of graft right ventricular myocardial dysfunction may prove troublesome or result in haemodynamic instability or catastrophic low cardiac output states. It may be necessary therefore to tide the patient over this temporary setback with a combination of various therapeutic options selected on the basis of careful clinical examination and investigation (Table 95.6). Most complex situations are assisted by or absolutely require the use of echocardiography.
Table 95.6 Possible support options for postoperative care of the complicated cardiac transplant recipient
| Treatment | Directed at | Based on |
|---|---|---|
| Inotropic support, e.g. milrinone or epinephrine | Poor contractility of LV, RV or both LV and RV | Elevated filling pressures, low cardiac output, echocardiography (TTE or TOE) |
| Pressor support, e.g. norepinephrine | Low systemic arterial blood pressure despite adequate filling pressures and supported contractility | Arterial pressure monitoring, cardiac output and TTE or TOE |
| Heart rate support with chronotropic drugs (e.g. isoprenaline or milrinone) or pacing | Low intrinsic grafted heart rate | Heart rate less than 90 in the first 48 hours usually symptomatic and indication for support |
| Mechanical support, e.g. IABP | Poor LV function not responsive to other measures | Elevated LAP, low cardiac output, poor response to drugs, TTE or TOE |
| Temporary ventricular assistance – RVAD, LVAD or BiVAD | Very poor RV, LV or biventricular function | As above, no response to less invasive measures and where recovery or retransplantation may be an option |
| Inhaled nitric oxide | RV failure combined with reversible elevation of PVR | Filling pressures, PAP, TTE or TOE |
| Resternotomy | Catastrophic states where excessive bleeding or tamponade is suspected | Combination of observations but particularly TOE |
IABP, intra-aortic balloon pump counterpulsation; LAP, left atrial pressure (direct or indirect); LV, left ventricle; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RV, right ventricle; RVAD, LVAD, BiVAD, right, left or biventricular assist device support; TOE, transoesophageal echocardiography; TTE, transthoracic echocardiography.
IMMUNOSUPPRESSION
The details of the immunosuppression regimen will differ between transplant centres but the principles are the same.16 Immunosuppression is induced just prior to transplantation and then maintained permanently with a combination of drugs aimed at maximal effect and minimal toxicity. Episodes of suspected or proven rejection prompt additional temporary treatment.
Since the early 1980s the regime used by most centres has been triple therapy with ciclosporin, azathioprine and corticosteroids. The initial introduction of ciclosporin in 1979 was a major step, but the drug has significant problems; in addition to renal and hepatic toxicity, there is uncertain gut absorption and bioavailability (at best only 30%) which can be exacerbated by many commonly prescribed drugs.17 Alterations in gut function may seriously reduce plasma levels to the point at which rejection may occur. Drug interactions may result in toxic levels. Plasma levels of the drug should be monitored frequently, especially in the early perioperative phase and during any complicating illness. When the gut cannot be relied upon the intravenous formulation may be used with one-third of the oral dose given by intravenous injection over 2–6 hours. Modified formulations of the drug have allegedly improved bioavailability and stability of plasma levels.18
Ciclosporin works through interleukin-2 (IL-2) inhibition in T lymphocytes so its action is fairly specific. Tacrolimus is an alternative to ciclosporin and has similar potency, toxicity and monitoring requirements. Azathioprine is the other commonly used drug. It has a much broader T and B lymphocyte depression effect so marrow suppression is not surprisingly a major potential side-effect. The intravenous alternative to the commonly used oral preparation is highly irritant and when the oral route is not available it is usually best omitted or an alternative used. Mycophenolate is often substituted for azathioprine. It has a much more specific effect through suppression of purine synthesis in lymphocytes, and achieves lower incidence of rejection, but at the expense of greater risk of infections.19 Corticosteroids are very important at induction and for treatment of rejection episodes but otherwise the dose is tapered to minimise all the usual steroid side-effects.
Immunological treatment with antithymocyte globulin (ATG) derived from various species was traditionally reserved for the treatment of rejection episodes but newer monoclonal ATG-type drugs20 may prove more effective and less allergenic. Newer approaches with the promise of greater specificity and lower toxicity include agents such as daclizumab21 which appears to reduce episodes of rejection, but so far no convincing evidence of improved survival. The complexity of these issues makes it vital that all relevant treatment decisions are made by, or discussed with, the relevant transplant centre.
REJECTION
One or more episodes of rejection are experienced by the majority of recipients within the first 3 months after transplantation. The risk is subsequently negligible in successful grafts. The diagnosis may be suggested on clinical grounds but the gold standard remains histological examination of an endomyocardial biopsy. In some centres biopsies are performed on a routine basis, as well as when rejection is suspected. The right internal jugular vein is the preferred vascular access site for performing the biopsy so this should be considered when selecting line sites for general critical care purposes. The clinical indications or suggestions of rejection are very non-specific and include dyspnoea, weight gain, malaise, atrial arrhythmias, low voltage ECG and echocardiographic evidence of declining cardiac function. The biopsy is graded according to an internationally accepted system, but some centres have moved to a more algorithm-based approach to the patient where clinical features and monitoring of the immune response help to determine the frequency of biopsies.22,23
OTHER COMPLICATIONS
Infection
Opportunistic infections (commonly lung) account for many of the complications and for a significant proportion of readmissions. A recent study reported that 45% of infections were bacterial and less than 10% fungal; however, the associated mortalities were 40% for fungal and less than 10% for bacterial infections.24 Opinions vary as to the current significance of cytomegalovirus (CMV) infection. Some centres believe that CMV is a problem of the past because of better matching of CMV status, and more effective and potent prophylaxis and treatment with ganciclovir when indicated.25 However, there is still significant risk of severe acute viral illness,26 and a possible link between acute viraemic episodes and subsequent damage to the graft and CAV.27
Malignancy
The transplant recipient has a hundredfold increased risk of new malignancy (around 1–2% per year) compared to age-matched controls. The majority are skin tumours (with substantially increased susceptibility to solar radiation) and lymphomas but any neoplasm may occur. Malignancy is one of the leading causes of death or late readmission to hospital and the risk of subsequent malignancy is a significant and complex factor in the selection of optimum immunosuppression.28
Cardiac allograft vasculopathy (CAV)
This is the main cause of death in the long term after heart transplantation and is a multifactorial process resulting in diffuse obliterative coronary atherosclerosis.29 The diffuse nature of the lesions makes revascularisation by angioplasty and stent, or by surgical bypass, difficult. Perhaps improvements in the control of rejection, management of CMV and drugs such as statins, calcium channel blockers and specific growth regulatory factors such as hepatocyte growth factor30 may help.
HEART–LUNG TRANSPLANTATION
SELECTION CRITERIA (Table 95.7)
Table 95.7 Heart–lung transplantation: donor selection criteria
POSTOPERATIVE CARE
COMPLICATIONS
Bleeding may occur due to extensive dissection and systemic pulmonary collaterals in congenital heart disease. Other early complications include tracheal anastomotic dehiscence, acute reperfusion lung injury (i.e. pulmonary oedema) due to long ischaemic times and infection. Heart–lung recipients have three times as many infections as heart recipients, and this contributes significantly to their higher mortality rate. Infection is the major cause of mortality in the first 6 months, and rejection thereafter.
SINGLE- OR DOUBLE-LUNG TRANSPLANTATION
Early attempts at single-lung transplantation (SLT) yielded only short-term survival.31 However, subsequent successes by the Toronto Group encouraged the development of double-lung transplantation,32 initially by the en bloc method with tracheal anastomosis. The extensive dissection required in the recipient and the high incidence of anastomotic problems encouraged development of bilateral sequential lung transplantation (BSLT), which has found wide favour.33 SLT is indicated for non-suppurative lung disease in a patient who does not have cardiac disease (e.g. emphysema from smoking or α1-antitrypsin deficiency, or fibrosing alveolitis). Whilst these conditions can also be managed by BLST, SLT provides satisfactory results and makes more efficient use of a limited donor pool. BSLT is indicated for suppurative and/or bilateral lung disease (e.g. cystic fibrosis and bilateral bronchiectasis). The merits of BSLT or HLT for these conditions are controversial. With HLT, the recipient’s heart may be used in a ‘domino’ procedure as a donor heart for a second recipient.34 Either BLST or a domino HLT allows the most efficient use of donor organs. Lung transplantation can be combined with kidney or liver transplantation.
POSTOPERATIVE CARE
SPUTUM RETENTION
Effective analgesia, aggressive physiotherapy and early mobilisation are essential to minimise this problem. Secretions below the anastomoses do not elicit a cough reflex and voluntary coughing is important.
LONG-TERM COMPLICATIONS
Obliterative bronchiolitis35 which may be a manifestation of chronic rejection may eventually lead to graft failure. Recurrent infections with Pseudomonas or methicillin-resistant Staphylococcus can be serious. After the first 6 weeks, infection with CMV, any fungus, protozoan or virus presents potential hazards. Chronic renal failure due to ciclosporin therapy may persist, but is not usually a major problem unless other complications occur. Most patients have a good quality of life with few complications. The improvement in quality of life after lung transplantation may be more important as a marker of success than bald survival figures.36
RESULTS OF CARDIOPULMONARY TRANSPLANTATION
A very good source of information on the results of intrathoracic transplantation can be found at www.ishlt.org and in more traditional publications37 such as the recent summary of results of transplantation in the UK.38 These figures indicate that survival is considerably better after heart transplantation than heart–lung or lung. Almost 90% of heart recipients are alive at 3 months as compared to around 75% of heart–lung and lung recipients. Around 70% of heart recipients are still alive after 5 years; 50% or less of heart–lung and lung recipients survive this long. While these figures are quite impressive and could improve with current trends in immunosuppression and general care, the main issue remains the gross disparity between the number of patients with end-stage cardiopulmonary disease and the ever-shrinking supply of donor organs. This is all the more reason to ensure that those patients who have got as far as to benefit from such a rare and precious opportunity receive high standards of medical care throughout their remaining life.
1 Brann WM, Bennett LE, Kekck BM, et al. Morbidity, functional status, and immunosuppressive therapy after heart transplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. J Heart Lung Transplant. 1998;17:374-382.
2 Hunt SA. 24th Bethesda conference: cardiac transplantation. J Am Coll Cardiol. 1993;22(Suppl 1):1-64.
3 Aaronson KD, Schwartz JS, Chen TMC, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660-2667.
4 Glenn E, Hill DJ. Advances in mechanical bridge to heart transplantation. Curr Opin Organ Transplant. 2000;5:126-139.
5 Barnett DB. Beta blockers in heart failure: a therapeutic paradox. Lancet. 1994;343:557-558.
6 Packer M, Coats AJ, Fowler MB, et al. Carvedilol prospective randomized cumulative survival study group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
7 Wasson S, Voelker DJ, Vesom P, et al. Cardiac resynchronization therapy for CHF. Postgrad Med. 2006;119:25-29.
8 Rose EA, Gelinjns AC, Moskowitz AJ, et al. for the REMATCH Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345:1435-1443.
9 Pennington DG, Oaks TE, Lohmann DP. Permanent ventricular assist device support versus cardiac transplantation. Ann Thorac Surg. 1999;68:729-733.
10 Stevenson LW, Shekar P. Ventricular assist devices for durable support. Circulation. 2005;112:111-115.
11 Clark NJ, Martin RD. Anesthetic considerations for patients undergoing cardiac transplantation. J Cardiothorac Anaesth. 1988;2:519-542.
12 Stein KL, Darby JM, Grenvic A. Intensive care of the cardiac transplant recipient. J Cardiothorac Anesth. 1988;2:543-553.
13 Cooper DKC, Lidsky NM. Immediate postoperative care and potential complication. In: Cooper DKC, Miller LW, Patterson GA, editors. The Transplantation and Replacement of Thoracic Organs. Dordrecht: Kluwer; 1996:221-228.
14 Borow KM, Neumann A, Arensman FW, et al. Cardiac and peripheral vascular responses to adrenoreceptor stimulation and blockade after cardiac transplantation. J Am Coll Cardiol. 1989;14:1229-1238.
15 Pope SE, Stinson EB, Daughters CT, et al. Exercise response of the denervated heart in long term cardiac transplant recipients. Am J Cardiol. 1980;46:213-218.
16 Hosenpud JD. Immunosuppression in cardiac transplantation. N Engl J Med. 2005;352:2749-2750.
17 Aziz T, El-Gamel A, Keevil B, et al. Clinical impact of Neoral in thoracic organ transplantation. Transplant Proc. 1998;30:1900-1903.
18 Cooney GF, Jeevanandam V, Choudhury S, et al. Comparative bioavailability of Neoral and Sandimmune in cardiac transplant recipients over 1 year. Transplant Proc. 1998;30:1892-1894.
19 Kabashigawa J, Miller L, Renlund D, et al. A randomized controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation. 1998;66:507-515.
20 Beniaminovitz A, Itescu S, Lietz K, et al. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med. 2000;342:613-619.
21 Hershberger RE, Startling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med. 2005;352:2705-2713.
22 Billingham ME, Cary NRB, Hammond ME, et al. A working group for the standardisation of nomenclature in the diagnosis of heart and lung rejection; Heart Study Group. J Heart Lung Transplant. 1990;9:587-593.
23 Itescu S, Tung TC, Burke EM, et al. An immunological algorithm to predict risk of high-grade rejection in cardiac transplant recipients. Lancet. 1998;352:263-270.
24 Aziz T, El-Gamel A, Krysiak P, et al. Risk factors for early mortality, acute rejection, and factors affecting first-year survival after heart transplantation. Transplant Proc. 1998;30:1912-1914.
25 Vuylsteke A, Wallwork J. The heart-transplanted patient in the intensive care unit: last news before the millennium. Curr Opin Critical Care. 1999;5:422-426.
26 Singh N. Infections in solid organ transplant recipients. Curr Opin Infect Dis. 1998;11:411-417.
27 Valantine HA. Cytomegalovirus infection and allograft injury. Curr Opin Organ Transplant. 2001;6:305-309.
28 O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25:1186-1191.
29 Ramzy D, Rao V, Brahm J, et al. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48:319-327.
30 Yamaura K, Ito K, Tsukioka K, et al. Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation – induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation. 2004;110:1650-1657.
31 Derom F, Barbier F, Ringoir S, et al. Ten-month survival after lung homotransplantation in man. J Thorac Cardiovasc Surg. 1971;61:835-846.
32 Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med. 1986;314:1140-1145.
33 Kaiser LR, Pasque MK, Trulock EP, et al. Bilateral sequential lung transplantation: the procedure of choice for double lung replacement. Ann Thorac Surg. 1991;52:438-446.
34 Yacoub MH, Banner NR, Khaghani A, et al. Heart–lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Transplant. 1990;9:459-466.
35 de Hoyos AL, Patterson GA, Maurer JR, et al. Pulmonary transplantation. Early and late results. J Thorac Cardiovasc Surg. 1992;103:295-306.
36 Anyanwu AC, McGuire A, Rogers CA, et al. Assessment of quality of life in lung transplantation using a simple generic tool. Thorax. 2001;56:218-222.
37 ISHLT. The registry of the International Society for Heart and Lung Transplantation: Twenty third annual report. J Heart Lung Transplant. 2006;25:869-911.
38 Anyanwu AC, Rogers CA, Murday AJ, et al. Intrathoracic organ transplantation in the United Kingdom 1995 to 1999; results from the UK cardiothoracic transplant audit. Heart. 2002;87:449-454.
