Primary Graft Dysfunction (PGD)

The transplant process from the declaration of death in the donor, to organ harvesting, cold storage and finally reperfusion in the recipient places a huge stress on the organ. All of these essential steps may create an inflammatory milieu that increases the possibility of alveolar oedema. The absence of lymphatic drainage in transplanted lungs, the primary mechanism for clearing excess alveolar fluid, means that the lung is exquisitely sensitive to these fluid shifts.

Primary graft dysfunction (PGD) is the syndrome complex that describes the early allograft dysfunction (<72 hours) and is the largest cause of early mortality. It is clinically manifest by progressive hypoxaemia associated with radiological infiltrates, and shares many similarities with acute respiratory distress syndrome (ARDS) in non-transplanted lungs. The syndrome is graded according to the International Heart and Lung consensus document (Table 41.1).

It is important to exclude other causes of early allograft dysfunction such as infection, volume overload, torsion of the lung or compromise of the pulmonary venous anastomosis, and acute rejection. In the majority of cases with grade 1 or 2 dysfunction, a relatively benign course is followed. However, the presence of persistent grade 3 PGD (>72 hours) is associated with a poor prognosis with estimates of 1-year survival varying from 30 to 60% and reduced long-term survival. A number of potential risk factors have been identified which include: recipients with PH, IPF, sarcoidosis or donors with obesity, older age, smoking, high alcohol intake, and possibly the use of cardiopulmonary bypass. Treatment of PGD is principally about careful fluid balance with supportive measures for oxygenation and haemodynamics. Aggressive diuresis and protective lung ventilation are the cornerstones of management for milder grades. For PGD grade 3, in addition to the above support, measures such as venovenous extracorporeal membrane oxygenation may be required (Figures 41.1 and 41.2). Some experimental approaches have included instillation of surfactant directly into the lung. Other potential treatments that are being explored include aspirin, statins, stem cells and aprotonin.

Figure 41.1 PGD grade 3 at 48 hours. The patient is very hypoxic despite being intubated and ventilated and is requiring ECMO support. The X-ray demonstrates extensive bilateral infiltrates.

Figure 41.2 PGD grade 3 at 1 week. The patient remains intubated and ventilated but with clearance of the alveolar oedema and without ECMO support.

Infections

The second biggest cause of early mortality in lung transplant recipients in the ICU after PGD grade 3 is infection. The lung transplant recipient is particularly vulnerable to infection as the allograft is open to the atmosphere and a number of the usual defence mechanisms are compromised. Foremost of these are the impairment of mucociliary function, reduced cough, pain and compromise of the innate and adaptive immune responses by immunosuppression. In addition, the use of mechanical ventilation along with the multiple invasive catheters required to manage the patient are portals for entry for infection in an immunosuppressed patient. This vulnerability extends across the whole microbial constellation and means that susceptibility to bacterial, fungal and viral infections is increased. Whilst opportunistic infections with low virulence organisms such as Pneumocystitis jirovecii (PCP) can be problematic it should be remembered that the most common infections in this group are the same as for other critically ill patients. This high-risk profile is managed early post transplant with prophylaxis with broad spectrum antibiotics, oral and nebulised antifungals and target antiviral agents.

Bacterial Infections

Cultures are taken from the donor at the time of harvesting and the generic universal prophylactic antibiotic regime is adjusted if these are positive. Many recipients will have pre-existing respiratory infections that may have antibiotic resistances. This is particularly an issue in CF patients who are often colonised chronically with Pseudomonas aeuroginosa, which is present in the upper airways and often recolonises the new lungs. This is managed with a pre-existing agreed antibiotic protocol and usually consists of at least two anti-pseudomonal agents that are given for 2 weeks post transplantation.

Viral Infections

The desired T-cell inhibitory effects of the post- transplant immunosuppression increase the susceptibility to and reduce the recipient’s capacity to deal with viral infections. Cytomegalovirus (CMV) is the commonest viral pathogen in lung transplant recipients and is associated with increased risk of chronic rejection in patients who develop CMV pneumonitis. The greatest risk is in CMV mismatched patients who are CMV naive and receive a positive organ. All CMV mismatched patients and positive patients receive prophylaxis with initially ganciclovir and subsequently valganciclovir.

Fungal Infections

Fungal infections cause significant morbidity and mortality in recipients post lung transplant. Lung transplants are particularly vulnerable to Aspergillus fumigatus infections of the airways. This can range from anastomotic infections that can result in airway complications to Aspergillus trachea-bronchitis (Figure 41.3). Fortunately, angioinvasive aspergillosis is a rare complication. To combat this potential complication, early post transplant most patients receive antifungal prophylaxis. Practices vary according to the risk profile of the centre. We employ both topical nebulised amphotericin and oral itraconazole until there is airway healing (Figure 41.4).

Figure 41.3 Bronchoscopic appearance of a right bronchial anastomosis, demonstrating a severely ischaemic airway with superadded Aspergillus infection.

Figure 41.4 Extensive left sided Aspergillus bronchopneumonia complicating chronic rejection in a lung transplant recipient.

COPD

COPD remains the most common indication for lung transplantation in the UK. With the rapid developments occurring in all areas of medicine leading to increasingly complex and aged patients comes the potential for these patients to be more frail. Although not exclusively a feature of age, it is recognised that a significant proportion of elderly patients will have features of frailty and as such this is likely to be an increasingly relevant clinical concern. Increasing understanding of the impact of frailty on outcomes is emerging, suggesting that determination of frailty may help to guide the appropriateness of therapy in individuals. Currently frailty is not formally quantified in lung transplantation. A number of studies have highlighted its potential utility in determining outcomes in potential recipients. Early studies have suggested that patients with frailty syndrome are more likely to develop complications and be removed from the waiting list prior to transplantation.

Cystic Fibrosis

CF patients have markedly altered pharmacodynamics with rapid processing of a number of classes of medications. This is particularly evident in the early postoperative period when the requirements for analgesia may be very high. A delicate balance between comfort and respiratory depression may be difficult to achieve, often necessitating the need for either an epidural or patient controlled analgesia. The need for opiates can increase the inherent propensity for bowel blockages in some CF patients and can be a very difficult perioperative issue, which can have a major impact on their outcomes.

Idiopathic Pulmonary Fibrosis (IPF)

Patients with IPF have fibrosis of the lungs which results in shrinkage of the lung volumes and a consequence of this is a stiff and relatively poorly compliant chest. Post transplant these patients often have small stiff chests that require time to accommodate to the new lungs. This may require protracted ventilation and gentle weaning.

Pulmonary Hypertension (PH)

Patients with PH have the most difficult perioperative course with the worst 30-day survival. The presence of PH is an independent risk factor for PGD, in addition the preoperative anticoagulation and selective pulmonary vasodilators all add significantly to the bleeding risk. The right ventricle (RV) in these patients has accommodated to chronic strain and is used to high filling pressures. The principle of drying the lungs out and keeping the right sided filling low often means that the RV function is severely compromised and may need support with inotropes. These issues are the main reason for increased early mortality and morbidity. However, it is reassuring that once through this difficult period patients do have good median and long-term survival.