1

Describe the history of pulmonary transplantation

The first pulmonary transplant was performed in 1963 (Hardy, Mississippi, USA) as a single-lung transplant but the patient died after 18 days.

Over the next 17 years, 38 lung transplants were carried out in 20 institutions but with universally poor outcomes.

As bronchial anastomotic breakdown was the main problem, heart-lung transplantation was introduced, as it involved a safer tracheal anastomosis, due to the systemic bronchial collaterals in the heart-lung bloc.

The first heart-lung transplant was performed in 1981 (Reitz, Stanford, USA) for idiopathic pulmonary arterial hypertension.

During this period, cyclosporine was introduced as an immunosuppressive agent, which dramatically improved results in all solid organ transplants.

The first successful single-lung transplant was performed in 1983 (Cooper, Toronto, Canada) and was followed a few years later by bilateral sequential-lung transplantation. These operations remain very similar today, rendering heart-lung transplantation unnecessary, except in patients with true concomitant heart failure.

The worldwide volume of lung transplantation has increased significantly to over 4000 cases per annum reported to the International Society for Heart & Lung Transplantation (ISHLT), with progressively improving outcomes.

2

What are the indications for lung transplantation?

Patients with chronic, end-stage respiratory failure, without significant pathology in other systems, a prognosis of approximately 2 years’ survival and symptomatic with New York Heart Association (NYHA) Class III or IV, should be referred for lung transplant assessment.

There is the concept of a transplant window where the patient’s lung condition is advanced enough to merit transplantation but overall condition is not so poor that they will not be able to rehabilitate afterwards.

Although a spectrum of pulmonary diseases affecting the lung parenchyma, pulmonary vasculature or airways may be considered, there are four main conditions responsible for the majority (85%) of lung transplantation, with different indications for transplantation in each condition (see below):

a)

chronic obstructive pulmonary disease (COPD) or emphysema – most common indication for lung transplantation;

b)

idiopathic pulmonary fibrosis (IPF) or usual interstitial pneumonia (UIP);

c)

cystic fibrosis (CF) or other causes of suppurative lung disease;

d)

pulmonary arterial hypertension.

The remaining 15% of cases comprise a multitude of rarer conditions, including retransplantation, for which indications for transplant need to be individualised to the specific case.

3

What are the indications for lung transplantation in a patient with chronic obstructive pulmonary disease (COPD) or emphysema?

Although this can be a slowly progressive condition, where patients can remain stable for many years, there are, however, a number of predictors of worse prognosis, where patients would benefit from transplantation, including:

a)

BODE (body mass index, airflow obstruction, dyspnoea and exercise) index 7-10 (Table 1);

b)

hospitalisation with hypercapnia;

c)

forced expiratory volume in 1 second (FEV₁) <20% predicted, with diffusing capacity of the lungs for carbon monoxide (DLCO) <20% predicted or homogeneous emphysema, or an accelerated decline in FEV₁;

d)

secondary pulmonary hypertension or cor pulmonale.

4

What are the indications for lung transplantation in a patient with interstitial lung disease?

Although absolute values from lung function tests are generally unhelpful in predicting prognosis in this patient group, longitudinal changes in pulmonary function can be helpful, such as a 10% drop in FEV₁ over 6 months.

Most patients with significant symptoms are referred for transplantation once a diagnosis is made by histology or radiology, as the median survival is 3 years from diagnosis.

UIP on histology portends a more rapid progression, whereas patients with non-specific interstitial pneumonitis (NSIP) typically have a slower progression.

DLCO <40% or desaturation <88% on a 6-minute walk test implies a poor prognosis.

Where pulmonary fibrosis is associated with systemic conditions, such as the collagen vascular diseases, evidence of quiescence in the systemic disease is essential for transplantation to be considered.

5

What are the indications for lung transplantation in a patient with cystic fibrosis or other causes of suppurative lung disease?

FEV₁ <30%.

Rapid decline in FEV₁.

Frequent infective exacerbations with deteriorating BMI.

Oxygen dependency with a resting hypoxaemia (PaO₂ <55mmHg).

Hypercapnia.

Pulmonary hypertension.

A big issue in CF is colonisation with multi-resistant organisms. In most cases, no single organism is an absolute contraindication but in combination with other comorbidities, this may be a factor weighing against transplantation. Colonisation with Aspergillus, non-tuberculous mycobacteria and multidrug-resistant bacteria, especially Pseudomonas, is frequent and requires specialised microbiological input. Many units refuse patients infected with Burkholderia cepacia (especially cenocepacia, previously referred to as genomovar III) because of reported universally poor outcomes in these cases.

Younger females with CF have a worse prognosis.

6

What are the indications for lung transplantation in a patient with pulmonary arterial hypertension?

NYHA Class III or IV despite maximal medical therapy (including prostacyclin).

Hypoxaemia at rest.

Arrhythmias.

Syncopal attacks.

7

What are the absolute contraindications for lung transplantation?

Malignancy (other than cutaneous squamous or basal cell carcinoma) in the last 2 years and for some malignancies, such as breast carcinoma, up to 5 years.

Significant dysfunction of another major organ system.

Chronic extrapulmonary infection, including chronic active hepatitis B or C, or human immunodeficiency virus (HIV).

Significant spinal or chest wall deformity.

Poor compliance or absence of an adequate social support system.

Substance addiction, including tobacco use, within 6 months.

8

What are the relative contraindications for lung transplantation?

Age >65 years.

Critical or unstable clinical condition, such as the requirement for mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support (see below).

Severely limited functional status, with poor rehabilitation potential.

Colonisation with multi-resistant organisms.

Previous pleurodesis.

Other medical conditions, including diabetes mellitus, gastro-oesophageal reflux disease and coronary artery disease.

The application of these relative contraindications varies between different transplant units and remains in evolution as outcomes continue to improve.

Often, the presence of more than one relative contraindication may tip the risk-benefit balance against transplantation.

9

Should patients requiring ventilator or extracorporeal membrane oxygenation support undergo transplantation?

As the best outcomes following lung transplantation are achieved by ambulatory patients with a chronic pulmonary condition, as compared to critically unstable patients, these patients were traditionally turned down for transplantation.

The improved ability to support these acutely deteriorating patients with either ventilatory or ECMO support, however, combined with an increased emphasis on ‘transplant benefit’ (which assesses post-transplant survival as well as the avoidance of waiting list mortality), has led to a greater acceptance of the role of lung transplantation in these patients.

Although 1-year survival following transplantation is lower (50-60% as compared to 80% in chronic patients) and in-hospital stays are greatly increased, the longer-term results once these patients have got through the procedure (‘conditional’ survival) appear to be comparable.

As these patients would otherwise have a 100% mortality, the ‘transplant benefit’ measure of outcome does allow for the use of organs for these patients, which are currently the limiting factor in transplantation volume.

It seems clear, however, that these patients need to be carefully selected, with short support periods, evidence of physical activity whilst on support and prior transplant assessment, all factors which are associated with better outcomes.

10

Which patients are suitable for organ donation?

The standard procurement procedure is to obtain the lung by donation after brainstem death (DBD) in donors with:

a)

PaO₂ >300mmHg (39kPa) on FiO₂ 1.0 and PEEP 5cm H₂O;

b)

age <60 years;

c)

no history of respiratory disease or smoking;

d)

clear chest radiograph;

e)

no evidence of aspiration or purulent secretions;

f)

no fungi or Gram-negative bacilli on microscopy;

g)

predicted total ischaemic time should not exceed 6 hours.

Once the DBD donor is legally declared dead by brainstem testing, they are taken to theatre, ventilated, with a good circulation, where their organs can be assessed and procured in a controlled manner.

Increasingly, organs are obtained by donation after circulatory death (DCD), where donors have not been certified dead by brainstem death criteria but by cessation of their heart beat. These are classified according to the Maastricht system (Table 2).

It is Class III DCD donors who are most relevant to lung transplantation, with increasing numbers performed worldwide with comparable outcomes to standard DBD donors.

In the Class III DCD donors, ventilatory and pharmacological interventions are stopped, resulting in a decline leading to cardiac arrest after a variable period.

Once death is declared by cardiopulmonary criteria, there is a stand-off period of around 5 minutes, after which the donor is taken to theatre, where organs are then assessed and procured in a more hurried manner than in DBD donors.

The DCD donor organs suffer a longer warm ischaemic period prior to procurement but the lungs appear to tolerate this.

There is an advantage to the DCD lungs in avoiding the injury caused by brainstem death in which a catecholamine surge induces endothelial leakage and pulmonary oedema in the DBD donor.

Currently, there is no observed difference in early- or medium-term outcomes between DCD and DBD donor lungs.

If other criteria of donor acceptability are met, such as adequate oxygen transfer and the absence of morphological abnormality, the donor pool can be expanded to include patients (extended criteria donors) with:

a)

increasing age;

b)

smoking history;

c)

bronchial secretions that clear on suctioning;

d)

primary brain tumours with no evidence of metastases;

e)

more prolonged periods of ventilation prior to procurement.

In addition, donors with predicted ischaemic times up to 12-14 hours may also be considered.

Similar to recipient selection, individual centres vary in their acceptance criteria. As before, however, it is frequently when there is more than one variable outside of the ideal range that the balance is tipped against the safe use of the organ. For example, it is well known that there is a negative interaction between advanced donor age and ischaemic time.

11

What are the principles of donor lung procurement?

Donor lung procurement usually occurs in the context of heart and multi-organ procurement.

Flexible bronchoscopy is performed to exclude aspiration and significant secretions.

Median sternotomy is carried out, with the incision extending down to the pubis.

The pericardium and both pleurae are opened.

The lungs are examined, palpated and areas of atelectasis are recruited by manual ventilation.

An arterial blood gas is obtained with the donor ventilated using 100% oxygen and a positive end-expiratory pressure (PEEP) of 5cm H₂O. A minimum PaO₂ of 300mmHg (39 kPa) is usually required for suitability.

Occasionally, selective pulmonary vein sampling for blood gas analysis may be performed to better localise areas of lung unsuitable for transplantation.

Once all procuring teams are ready to proceed, the donor is fully heparinised (30,000 IU) and a 500μg bolus of prostacyclin is administered into the pulmonary artery to reduce reflex hypothermic vasoconstriction.