11 Cardiothoracic transplantation

Christopher H. Wigfield, Stephen C. Clark, Asif Hasan

Introduction

Within 40 years heart transplantation has evolved from an experimental procedure to an effective therapeutic strategy for end-stage heart disease. In the current era heart transplant programmes around the world are showing medium-term survival in excess of 80–85%.¹ Significant improvements have been achieved, particularly for 30-day and 1-year mortality. 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 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.

Indications for heart transplantation

The reason for undertaking heart transplantation is to prolong life and to improve its quality. The indications for adult heart transplantation have remained essentially unchanged over the last three decades and at present are predominantly coronary-related heart failure (38%) and cardiomyopathies (45%). Valvular (2%) and miscellaneous diagnoses (10%), adult congenital (3%) and re-transplantation (2%) constitute the rest.¹

The indications for paediatric heart transplantation (<16 years) are different to adults. In our series of 153 paediatric heart transplants (1987–2008), 60% were undertaken for cardiomyopathy and 40% for congenital heart disease.

Aetiology of heart disease

Introduction

End-stage heart failure has become a major medical problem.⁴ The increasing prevalence with 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.

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:

1 Does the patient fulfil the selection criteria for heart transplantation?

2 Are there any contraindications to transplantation?

3 Is there any possibility of any other treatment option?

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

• 12-lead ECG

• Chest X-ray (PA and LAT)

• 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 (VO_2max)

• 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)

4 Physiotherapy assessment

An assessment and education package from the transplant physiotherapist with regard to exercise pre- and post-transplant, and postoperative chest care

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.

Mancini et al.⁸ and others⁹^–¹¹ 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.⁹ This score, along with maximal oxygen consumption (VO_2max) and clinical assessment, can bring some rigour to the selection process for transplantation.

Deng et al. showed that cardiac transplantation does not benefit patients with medium- and low-mortality risk as assessed by calculation of heart failure survival score.¹⁰

More recent evidence suggests that for patients with ejection fraction <20% and severely reduced functional capacity, best outcomes are achieved in the absence of comorbidities that raise perioperative mortality risks. The predictors of survival have been refined and patients requiring inotropic or mechanical support to maintain systemic perfusion in advanced heart failure have a good prognosis with heart transplantation.¹

Contraindications

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

1 Factors that increase perioperative mortality, e.g. elevated pulmonary vascular resistance.

2 Factors affecting long-term prognosis.

Box 11.2 Contraindications for heart transplant

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. Heterotopic transplantation can also be considered in these circumstances to overcome elevated pulmonary vascular resistance.¹¹

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.

Biventricular pacing

In 20–30% of patients with symptomatic heart failure there is a prolonged PR interval, wide QRS complexes and intraventricular conduction disorders leading to a discoordinate contraction pattern. The result is earlier atrial contraction causing mitral regurgitation. This is further compromised by paradoxical septal motion due to wide QRS and conduction abnormalities. Biventricular pacing has been shown to synchronise contractility and improve the functional class of patients.¹⁵^–¹⁷ We have used biventricular pacing in several of our patients with improvement in functional class and subsequent delisting from transplantation.

Implantable cardio defibrillators

Implantable defibrillators have had benefical impact on survival of patients with implantation including previous ventricular arrhythmias and poor ejection fraction status.¹⁸

Novel end-stage heart disease therapeutics

New agents to treat end-stage disease have become available and the benefit of antagonists to stabilise symptoms and delay patients entering waiting lists for transplantation has been evident. A recent landmark publication by the American College of Cardiology has confirmed the advanced administration of medical therapeutics in a large cohort of patients and specific guidelines have been widely implemented.^19,²⁰ Other novel therapeutics are in various stages of clinical trials.

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.^21,²² The limiting factors for this approach, either as a bridge to transplantation or as destination therapy, are availability and device selection. More recently the role of assist devices for right heart failure indications is evolving.

Donor selection and matching

Specific guidelines for optimal donor selection have been published by the International Society for Heart and Lung Transplantation.²³

Management of the potential organ donor has evolved and requires a multidisciplinary approach.²⁴ Donor allocation for hearts in the UK is run by UK Transplant (UKT). 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 60 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.²⁵ 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.²⁶ 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 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.²⁷

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 are considered for transplantation. Glioblastoma patients and those with shunts are not considered.

A history of intravenous drug abuse would disqualify the donor, but an exception can be made in the very ill recipient and a normal echocardiogram of the donor heart 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. 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, 30% undersizing is acceptable, although much smaller donors have been reported with satisfactory outcome.^28,²⁹ 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.

ABO compatibility

ABO compatibility is required to avoid hyperacute or accelerated acute rejection. Rhesus incompatibility is acceptable. The only ABO exception would be the A₂ subgroup as donors with this subgroup may be less prone to producing hyperacute rejection, because A₂ antigen is not readily displayed on the endothelial surface of the heart. However, in the paediatric group successful heart transplantation has been undertaken in the presence of ABO incompatibility.¹⁸ This is possible as the immune system in infants is immature and their anti-A and anti-B titres remain low until 12–14 months of age. We have successfully undertaken 10 transplants in children with ABO incompatibility.³⁰ The oldest was 18 months old when heart transplantation was performed.

Immunological matching

The rationale for undertaking immunological testing is to identify potential recipients with circulating anti-HLA antibodies to avoid mismatch between donor and recipient that could lead to hyperacute or accelerated acute rejection (see Chapter 4).

Common causes of sensitisation are pregnancy, prior blood transfusion or insertion of a ventricular assist device. Rarely, a patient may be sensitised for unknown reasons. The test is considered positive if a 10% threshold is reached on testing the donor serum with the control group. When the recipient has detectable panel-reactive antibodies (PRAs), a prospective crossmatch is undertaken, which has implications regarding the timing of transplantation and in our experience does disadvantage the recipient. The long-term results of recipients having more than 25% PRAs show that they are more prone to rejection.³¹

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.³²

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 due to coagulopathy 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. has remained the standard operation for 30 years.³³

Figure 11.1 Division of the right atrium to create superior and inferior vena caval cuffs for bicaval technique. The great vessels are divided as in the standard orthotopic method.

Figure 11.2 Completion of bicaval transplant technique, showing the inferior vena caval, aortic and pulmonary artery anastomoses.

Reproduced from Kirklin JK, Young JB, McGriffin DC. Heart transplantation. Edinburgh: Churchill Livingstone, 2002; Ch. 10.8, p. 343. With permission from Churchill Livingstone.

The most significant modification to heart transplant procedure has been the use of a bicaval technique. This results in less tricuspid regurgitation and better haemodynamic performance of the implanted heart.³⁴