Cardiothoracic transplantation

11


Cardiothoracic transplantation




Introduction


The first successful heart transplantation undertaken on December 1967, at least in the public eye, represents a defining moment in surgical treatment of heart diseases in the 20th century. Since then heart transplantation has evolved from an experimental procedure to an effective therapeutic strategy for end-stage heart disease. In the current era the median survival or half-life (the time at which 50% of transplant recipients remain alive) is 11 years. For adult and paediatric patients surviving to 1 year after transplant, the median survival has reached 14 years. Many hundreds of patients have now lived past 25 years since their transplant procedure.1


Nevertheless, the success of heart transplantation has raised expectations that under present circumstances it cannot fulfil. On one hand, due to improved management of ischaemic heart disease and increased longevity, the number of patients with heart failure is growing.2 On the other hand, there is a decrease in the number of cardiac transplantations due to donor organ constraints. This disparity between the number of donors and potential recipients has stimulated research to find new alternatives to transplantation. However, these have so far had little impact on the current practice of heart transplantation. The advent of novel therapeutics and surgical options for impaired ventricles may in selected patients defer consideration for transplantation, and clinical guidelines have been provided for this purpose.3 The contemporary practice of heart transplantation with respect to indications, surgical techniques, and donor and recipient management will now be reviewed.




Aetiology of heart disease



Introduction


End-stage heart failure has become a major medical problem.2 The increasing prevalence with the rising age of the general population in most societies accounts for a large proportion of healthcare spending due to frequent hospital admissions.5 In the aetiology of congestive heart failure (CHF), we differentiate primarily ischaemic from other cardiomyopathies and congenital heart disease during transplant candidate assessment.



Ischaemic heart disease


This constitutes the largest group requiring heart transplantation. These patients can present in a variety of ways, from being acutely ill after myocardial infarction on mechanical support to being chronically ill with heart failure with or without previous surgical or catheter-based intervention. Unfortunately, there are no conclusive prospective studies comparing conventional treatment methods with heart transplantation to provide guidance in risk–benefit assessment. A digest of current thinking would indicate that heart transplantation would definitely be indicated in a patient with severe heart failure with poor ventricular function (ejection fraction < 15%), symptoms of heart failure with little or no angina, diffuse coronary artery disease, absence of reversible ischaemia and/or poor right ventricular function (ejection fraction < 35%). What is clear is that patients with ischaemic cardiomyopathy who develop heart failure are likely to have a worse prognosis than non-ischaemic patients.6



Non-ischaemic cardiomyopathy


This group includes a variety of aetiologies with marked left and/or right ventricular dysfunction. Disease processes that result in changes in heart muscle are classified as: (a) dilated cardiomyopathy; (b) hypertrophic cardiomyopathy; (c) restrictive cardiomyopathy; and (d) arrhythmogenic right ventricular dysplasia. In patients with non-ischaemic cardiomyopathy, transplantation is indicated if there is failure of aggressive medical treatment.


Certain types of cardiomyopathies can show reversibility, and a period of observation with medical treatment should be tried before listing. These include lymphocytic myocarditis, peripartum cardiomyopathy, hypertensive cardiomyopathy and alcoholic cardiomyopathy.7


Indications for paediatric patients are similar; however, the risk of death is highest during the first 3 months after presentation, therefore failure of aggressive medical treatment early in the course of the disease should lead to early assessment for transplantation. Acute myocarditis needs a special mention as the finding of acute inflammation on biopsy is a favourable prognostic sign for subsequent recovery.8




Recipient evaluation and selection


Patients are evaluated for transplantation once a referral has been made. We admit the patient for a few days for assessment. During this period there is a systematic evaluation of both the physical and psychological state of the patient; it also gives an opportunity to develop a rapport between the patient, relatives and the multidisciplinary team. The protocol used in our own centre for assessment is summarised in Box 11.1. The assessment process is designed to answer the following questions:



Box 11.1   Recipient assessment protocol for heart transplantation



1 Full medical assessment


Full history and physical examination. Investigations include:



• Full blood count, platelets and coagulation screen


• Blood group


• Urea and electrolytes, liver function and thyroid function


• Microbiology – sputum, midstream specimen of urine (MSU), nose/throat/axilla/perineum swabs for culture


• Full viral screen (with patient consent)


• Fasting glucose and lipids


• Twelve-lead ECG


• Chest X-ray (posterior–anterior and lateral)


• Spirometry


• Echocardiogram


• Chromium EDTA glomerular filtration rate (GFR) (renal opinion and abdominal ultrasound would be required if GFR < 32.5 mL/min)


• Estimation of peak oxygen consumption (VO2max)


• Right heart catheter to assess filling pressures and calculate pulmonary vascular resistance, after discussion with the transplant cardiologist (as per protocol)


• Bone density (if > 50 years or symptoms)


• Urine flow rate/residual (if male > 50 years or symptoms)


• Carotid/peripheral artery Doppler (if symptoms)







Selection criteria


The process of selection of patients for transplantation remains an inexact science. In the majority of cases the referral for transplantation is of a patient with chronic heart failure. In these cases there is remarkable divergence of opinions when a patient should be listed for heart transplantation, further compounded by a paucity of evidence to guide day-to-day clinical practice. Avoidance of transplantation when a patient is ‘too good’ has important prognostic indications, as the 10-year survival after orthotopic heart transplantation remains 50% in most centres.



image


Mancini et al.8 and others911 showed that patients with a peak exercise oxygen consumption of < 14 mL/kg/min had a significantly higher mortality than patients with a peak exercise oxygen consumption of > 14 mL/kg/min.


The limitation of this technique is that it can be influenced by body composition, individual motivation or general deconditioning. Some centres have incorporated the heart failure survival score (HFSS) to their preoperative assessment. The score consists of seven variables – resting heart rate, left ventricular ejection fraction, mean arterial blood pressure, interventricular conduction delay, peak exercise oxygen consumption (VO2), serum sodium and ischaemic cardiomyopathy. Using these variables Aaronson et al. developed a mathematical model to predict outcome with medical management.10 This score, along with maximal oxygen consumption (VO2max) and clinical assessment, can bring some rigour to the selection process for transplantation.



image


Deng et al.11 showed that cardiac transplantation does not benefit patients with medium and low mortality risk as assessed by calculation of heart failure survival score.


Patients who are inotrope dependent and in persistent circulatory shock due to primary cardiac disorder undergo urgent assessment. The aim in these patients is to list them for urgent transplantation or consider ventricular assist device implantation.



Contraindications


Contraindications to heart transplantation are summarised in Box 11.2. These can be classed in three groups:




These exclusion criteria have continued to change with improvement in medical treatment and increasing experience with heart transplantation, and now successful outcome can be obtained in cases previously excluded. Some of the contraindications deserve special mention.


Pulmonary vascular resistance (PVR) of more than 6 Wood units has been considered an absolute contraindication to heart transplantation but with the introduction of nitric oxide, use of a bicaval anastomotic technique, early implantation of ventricular assist devices, and increasing use of perioperative phosphodiesterase inhibitors and isoprenaline, good results can be obtained in patients who formerly would not have been offered the opportunity of transplantation. Nevertheless, the presence of an elevated PVR should not be taken lightly as the donor right ventricle generally tolerates a systolic pressure of more than 50 mmHg poorly and would acutely fail. In our own practice a PVR > 3 Wood units would be considered a relative contraindication to transplantation. The transpulmonary gradient (TPG) (see Box 11.3) represents the pressure gradient across the pulmonary vascular bed and is independent of the pulmonary blood flow. Some consider the elevation of this above 14 mmHg as a more useful indication of significantly raised PVR as this is independent of the cardiac output, which may be poor in these patients. We rely more on this criterion and generally consider a fixed TPG of 12 mmHg and above as an absolute contraindication. In paediatric patients a higher TPG can be considered as it could be overcome with a larger sized donor heart.



Renal dysfunction is one of the most common problems encountered in the assessment of these patients. Multiple studies have shown that it is a major risk factor for mortality after heart transplantation. A common dilemma is to distinguish between renal dysfunction due to intrinsic renal disease or severe heart failure and aggressive diuretic therapy. It is essential to measure the glomerular filtration rate (GFR) and a low GFR may occasionally indicate renal biopsy to further elucidate the cause. Others have used measurement of effective renal plasma flow (ERPF) as an investigative modality, and less than 200 mL/min is considered indicative of major intrinsic renal dysfunction and an indication for combined heart and kidney transplantation, which can be peformed with good outcomes.12


Diabetic candidates have been shown to have good outcomes in the absence of significant end-organ damage (retinopathy, nephropathy, autonomic dysfunction and neuropathy or advanced peripheral vascular disease). Previously often excluded from heart transplantation, the 1- and 3-year survival, as well as rejection rates and infection prevalence achieved after transplantation, are comparable to non-diabetic recipients.


Compliance is the neurobehavioural capacity to adhere to a complex lifelong medical regimen. Non-compliance following heart transplantation can lead to major morbidity or death. Unfortunately, there are no proven psychological or sociological factors to predict poor compliance or adverse outcome after transplantation. Adherence to medical treatment and ability to keep appointments can provide some pointers towards compliance. Psychiatric disorders that impair compliance, such as severe depression or untreated schizophrenia, are contraindications to heart transplantation.13



Other options


It is not unusual to find patients who have been referred for transplantation to be suitable for alternative treatments. In addition, there are newer methods of treatment of heart failure in both medical and surgical disciplines being developed, and some of these patients could derive benefit from them.14 Some developments are worth mentioning.





Ventricular assist devices


Over approximately 15 years, ventricular assist device support has developed into a realistic option for selected patients with refractory congestive heart failure of various aetiologies. This has been established in the REMATCH trial, where medical management of New York Heart Association (NYHA) class IV heart failure patients was inferior to mechanical assistance when comparing 1- and 2-year survival.17,18 Current continuous flow devices with their low mechanical failure rate and fewer haematological complications are set to revolutionise our management of advanced heart failure.19 Currently these devices are only available for bridge to transplantation in the UK; however, with the decline in the number of heart transplants these devices may have to be considered as final destination for some patients.20



Donor selection and matching



Management of the potential organ donor has evolved and requires a multidisciplinary approach.22 Donor allocation for hearts in the UK is run by the Organ Donation and Transplantation arm (ODT) of NHS Blood and Transplant (NHSBT). The hearts are allocated on a pro-rata basis; however, a category of ‘urgent’ was created in 1999 to deal with acutely ill patients. Once a donor is identified, certain criteria apply before acceptance.



Donor age


An upper limit of 65 years is generally advocated and used by our own unit, but there is variation in other centres. The current mean age, including paediatric donors, at our programme currently is 44 years. It is important that donor age should not be viewed in absolute terms but should be considered along with other factors such as cardiac function, recipient urgency and projected ischaemic times. However, older donors are more likely to have coronary artery disease and there is increased mortality for the recipient if the heart has come from a donor over 40 years of age.1 The presence of coronary artery disease should not be considered an absolute exclusion criterion as satisfactory outcomes can be achieved with concomitant coronary revascularisation.23 United Network for Organ Sharing (UNOS) data from the USA show that in 1982 2.1% of donors were aged 50 years or greater but by 1994 this percentage had increased to 8.9% and has remained the same over the last 10 years.24 It remains difficult to evaluate pre-existing donor coronary artery disease at the time of organ procurement. Some centres advocate a single-plane coronary angiography (on table), but the availability and interpretation remain problematic.



Cardiac function


Brain death leads to myocardial changes with abnormalities seen on electrocardiogram (ECG) of ST segment elevation, T-wave inversion and Q waves, often signifying subendocardial ischaemia. Events following brain death, namely prolonged hypotension, cardiopulmonary resuscitation and high-dose inotropic support, also contribute to cardiac dysfunction, particularly acute right ventricular impairment. The assessment of cardiac function is undertaken by echocardiogram, Swan–Ganz catheter and finally by the surgeon procuring the organ. Troponin I may be useful in detecting donor myocardial injury and elevated levels are associated with impaired cardiac function.25


There is no consensus on what degree of inotropic support correlates with structural and functional damage sufficient to compromise graft function. It has been recommended that hearts should not be used if the inotropic requirements exceed 20 μg/kg/min of dopamine. Often, inotropes are used in conjunction with fluid infusions to fill a vasodilated circulation and bolster perfusion pressure. We utilise arginine vasopressin under these conditions and wean the inotropes. Failure to wean the inotropes under these conditions is a bad prognostic sign and suggests cardiac dysfunction. Donor hearts developing arrhythmias are not considered suitable.



Donor disease


Donors with an active infective focus are usually turned down. However, donors with a history of meningitis that has been adequately treated are considered for donation. Hepatitis C patients are not considered unless the recipient is positive for hepatitis C or is acutely ill on the urgent list. Hepatitis B donors with positive surface antigen are avoided, but core antibody-positive donors (surface antigen-negative) can be considered.


Donor hearts from donors with primary brain tumours should all be considered for transplantation. The risk of transmission of the tumour to the recipient is very small (≈ 1%) and only 1.5–2% for the more aggressive tumours or when there has been craniotomy or shunting.26


A history of intravenous drug abuse may disqualify the donor, but exceptions can be in the presence of negative serological viral testing. High-risk donors require careful evaluation as the routine enzyme-linked immunosorbent assay (ELISA) testing serology used does not achieve the same specificity as DNA-based tests.27 Chronic cocaine use causes cardiomyopathic changes and caution should be used in accepting hearts from such donors.



Size matching


As a general rule for routine adult heart transplantation with a normal PVR, 10% undersizing is acceptable, although much smaller donors have been reported with satisfactory outcome.28 In patients with a raised PVR deliberate oversizing is routinely undertaken to overcome pulmonary vascular resistance. In the paediatric group oversizing is often done to utilise all available hearts. In our last 30 consecutive paediatric transplants the average size discrepancy between donor and recipient was 150%, and in a cohort of patients who had a failing Fontan circulation as an indication for transplantation, the oversizing was 250%. The adverse consequences of oversizing are delayed sternal closure, collapse of the left lower lobe and systemic hypertension. However, all these factors can resolve with time and appropriate treatment.





Donor heart procurement


It is important to optimise the haemodynamic, metabolic and respiratory condition of the donor to maximise the yield of donor organs. This may entail using a multidisciplinary team to manage and optimise the donor before retrieval. Some poorly functioning hearts could be resuscitated by careful manipulation of inotropes and loading conditions of the heart. Using this strategy, up to 30% of such hearts can be successfully ‘resuscitated’ and used for transplantation.31


The thoracic organs are accessed by midline sternotomy; this might have already been performed by the liver retrieval team. It is important to secure haemostasis carefully and volume replacement should continue actively. This requires careful consideration of other organs procured, especially the lungs.


Whilst the abdominal dissection is being undertaken the pericardium is opened and the heart is inspected for its functional state, as well as the presence of any congenital abnormality. The heart is palpated to feel any thrill for valvular heart disease or any coronary plaques. When the mobilisation of abdominal organs is completed, heparin at a dose of 300 units/kg is administered. If a central line is in place, it is withdrawn. The superior vena cava is ligated and the inferior vena cava is completely divided. This allows the heart to exsanguinate into the right pleural cavity. The aorta is now clamped and cardioplegic solution is infused via the aortic root. We use 1 litre of St Thomas’s cold crystalloid cardioplegic solution; this is augmented with cold topical saline. The dose for paediatric donors is 30 mL/kg. During the administration of cardioplegia the right superior pulmonary vein is incised to decompress the left side of the heart.


Once the cardioplegia has been given, the cardiectomy can proceed further. The superior vena cava is incised above the previous ligature. The aorta is now divided below the innominate artery; this exposes the pulmonary artery, which is divided on the left side where the left pulmonary artery is attached to the pericardial reflection and the right pulmonary artery is divided behind the aorta. The left atrium is now incised at the level of the pericardial reflection. Due consideration to leave sufficient left atrial tissue along each pulmonary vein is essential when lungs are procured for transplantation.


The heart is now inspected for the presence of a patent foramen ovale and, if found, is oversewn. The heart is now packed inside three bags with cold saline in the intervening bags. The heart is then placed in a transport cooler packed in ice to be transported.



Heart transplantation (Figs 11.1 and 11.2)


The classical technique of orthotopic heart transplantation as described by Lower et al.32 and now modified to use the bicaval addition has remained the standard operation for 30 years.



The operation is undertaken with a midline sternotomy. Cardiopulmonary bypass (CPB) is established with right atrial venous cannulation to allow decompression of the heart; this allows for easier cannulation of superior and inferior venae cavae. The patient is then cooled to 32 °C. The cavae are now snared and the aorta is clamped. To facilitate bicaval anastomosis it is recommended that at this stage the interatrial groove is dissected to develop a cuff of left atrium. The cardiectomy proceeds with a right atrial incision, which runs parallel to the atrioventricular groove; care is taken at the inferior caval end of this incision to preserve as much tissue as possible to facilitate inferior caval anastomosis. An incision is then made in the roof of the left atrium to further decompress the heart before dividing the aorta just above the aortic valve. Retracting the heart downwards now exposes the pulmonary artery, which is again divided above the pulmonary valve. The superior vena cava is now divided just at its right atrial junction. The heart is now only attached to the pulmonary veins and via a small bridge of tissue to the inferior vena cava. The inferior caval attachment is divided, again being mindful of the inferior vena cava (IVC) cuff; the incision in the left atrium is now extended to encircle the pulmonary veins, leaving behind two pulmonary veins on each side attached with a bridge of tissue.


The donor heart is now prepared for implantation. The pulmonary veins are joined together by incisions removing any excess tissue, the pulmonary artery is cut back to its bifurcation, and a dose of blood cardioplegia is given in the aortic root. The donor and recipient atria are anastomosed with 3/0 polypropylene; care is taken not to leave excess tissue behind as it could be thrombogenic or can obstruct the pulmonary venous orifices. The suture line is not completed as a vent is left in the left atrium to take away the warm blood. The aortic anastomosis is now undertaken with a 4/0 polypropylene suture. At this stage the aortic cross-clamp can be removed to reduce the donor ischaemic time. De-airing is undertaken through the aortic root and a dose of steroids is given before the clamp is removed. This is a critical period as the heart has been reperfused after a prolonged period of ischaemia. The heart usually starts to beat, but if ventricular fibrillation occurs the heart is promptly defibrillated. Careful attention is paid to the perfusion pressures and the ventricle is kept decompressed; the atrial vent is left in until satisfactory contractility is resumed. The pulmonary artery anastomosis is next undertaken, care being taken in trimming of the pulmonary arterial cuff to avoid redundancy. The IVC and then the superior vena caval anastomoses are completed.


Once the implantation is complete the body temperature is brought back to normothermia. We would reperfuse the heart for at least 10 minutes of every hour of ischaemic time before making an attempt at weaning CPB. Weaning from CPB is undertaken carefully, avoiding distension of the right ventricle. Before closure of the chest, ventricular and atrial temporary pacing wires are attached, and a left atrial monitoring line is left in situ. Isoprenaline is frequently used for rate control and initial right ventricular afterload reduction.



Special situations





Perioperative management


The principles of early management of the heart transplant patient are: (a) to maintain graft function, specifically to recognise and manage right ventricular impairment early; (b) to establish adequate immunosuppression; (c) to prevent and treat early infections; and (d) to allow recovery of other system functions, such as renal function.



Graft function


Most patients will have reduced myocardial function after heart transplantation and would require inotropic support, which is usually weaned over 24–48 hours. However, some patients develop either right or left ventricular dysfunction. Development of right ventricular dysfunction is multifactorial. Initially, brain death-induced subendocardial ischaemia can occur in the donor. The right ventricle has a disposition to suffer the consequences of relative size mismatching of donor and recipient, especially related to the level of PVR after transplantation, inadequate myocardial preservation and discrepancy in size of the donor (smaller donor). The management of this would consist of adjusting preload, aggressive right ventricle (RV) afterload reduction and inotropic support. If the PVR is elevated, nitric oxide is added and in extreme cases a right ventricular assist device is used. It is important that an anastomotic complication is excluded by measuring the pressure gradient across the pulmonary artery suture line; surgical revision is indicated if the systolic gradient is > 10 mmHg.


Left ventricular dysfunction is again managed with adjustment in inotropic support; under rare circumstances the dysfunction can be life threatening and left ventricular assist may be required.



Immunosuppression


Triple therapy consisting of ciclosporin, azathioprine or mycophenolate mofetil and steroids is the standard regimen used by most centres. We employ induction therapy using equine antithymocyte globulin (ATG) in the paediatric group and in patients with severe renal impairment who are intolerant of ciclosporin. Tacrolimus has been used as a substitute for ciclosporin in patients with persistent rejection and in children with side-effects of ciclosporin, i.e. gingival hypertrophy and hirsutism. Newer immunosuppressive agents, such as rapamycin and interleukin-2 receptor antibodies (basiliximab and daclizumab), are being used in heart transplant rejection prophylaxis and treatment but have not yet found their place in routine immunosuppression protocols, despite a number of promising studies.


Monitoring of rejection following heart transplantation is crucial to short- and long-term survival of patients. The gold standard of rejection monitoring is endomyocardial biopsy. However, the histological findings of rejection are not uniformly present throughout the myocardium, and a high degree of clinical vigilance is needed in post-transplant follow-up of these patients. Approximately 7% of patients have an early rejection episode within 30 days of transplantation and at least 15% receive treatment for acute rejection within the first year.

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Jul 23, 2016 | Posted by in Aesthetic plastic surgery | Comments Off on Cardiothoracic transplantation

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