What’s new in lung transplantation

by Professor John Dark (pictured) – In contrast with that other thoracic organ the heart, activity and optimism in the pulmonary field are both increasing. Contemporay outcomes for selected groups of patients such as those with Cystic Fibrosis¹ show median survivals in excess of ten years, double the oft quoted Registry figures of the past.

This is still below what is routinely achieved with other organs, indicating considerable room for improvement at all stages after transplant. There have been advances in the understanding of late graft loss, usually due to progressive small airway obstruction – obliterative bronchiolitis (OB). Gastro-oesophageal reflux (GORD), often occult, is increasingly realised as an important, treatable cause of OB,² and for early cases, the macrolide antibiotic azithromycin appears to have benefit in stabilising the condition. The results of a UK randomised trial are imminent.

Primary Graft Dysfunction (PGD), an acute lung injury that combines pre-donation damage and the consequences of ischaemia-reperfusion, affects up to 20% of recipients and is fatal in almost half.  If survived, it is also a predictor of late graft failure – the peri transplant injury acts as a trigger for either heightened immune stimulation or disordered repair leading to fibrosis. This route, with epithelial-to-mesenchymal transformation, is common to other organ transplants.

The brain-death related injury in the donor is the principle reason why only about 20% of donor lungs are used for transplant. This particularly severe organ shortage is demonstrated by some sobering data from NHSBT. 194 adults were added to the lung transplant waiting list in 12 months of 2006-07. Three years later 51% had been transplanted, 6% still waited and 43% – some 83 patients – had either died or been removed from the list.

So a major challenge for the lung transplant community is to reduce damage to the lung at each of the early stages – in the donor, before implant and in the recipient. Solving these problems might result in more transplants with better lungs and many more surviving into the second decade. Some recent advances offer a real prospect of achieving all this!

Brain-death damages all donor organs, but particularly the lung, because of its huge endothelial surface. Traditional mechanical ventilation often exacerbated this injury. A randomised trial in Italy³ has shown that lung-protective ventilation, with low tidal volumes and pressures, doubled the number of lungs reaching criteria for transplant. There was also a small, non-significant, increase in the number of hearts, livers and kidneys from the same donors, probably because of a reduction in the overall inflammatory state in the donor. The recent Donor Care recommendations from NHSBT embrace this sort of approach, and we look for a significant effect in the UK.

Increasing numbers of donors are not brain-dead, but have a circulatory death after withdrawal of treatment – the DCD approach. One might expect their lungs to have suffered less initial damage, even though warm ischaemia might be an issue. Series from around the world have established that these DCD lungs are at least as good as DBD lungs.^4-5 Unpublished Australian data (Bronwyn Levvey), where 28% of all lung transplants are from DCD donors, showed a one-year mortality of only 10%, approaching half that for conventional donors. In the UK, where almost 400 out of less than 1100 total cadaveric donors were DCD, this represents a considerable opportunity. Last year less than 10% of our donated lungs came from the DCD route.

A signal problem with the DCD lung is that function cannot easily be measured – blood gas estimations can’t be done when there is no circulation! The decision to use a lung has in the past been very subjective, and heavily dependent on the experience of the surgeon. The technique of Ex-Vivo Lung Perfusion (EVLP) was developed to solve this particular problem. Initially championed by a Swedish group, it consists of a circuit to pump a blood-based fluid around the lungs, whilst gently warming and then ventilating them. Vascular resistance and airway dynamics are easily measured. An oxygenator is included in the circuit, but used to de-oxygenate the blood going into the lungs, simulating the clinical situation. When ventilated on 100% oxygen, blood gas measurements from the left atrium allow a real assessment of gas exchange.

This approach is ideal for objectively assessing the DCD lung. A group in Toronto have further refined EVLP, moving to an acellular perfusate, which permits pumping of the lungs for 12 or even 24 hours. They reported excellent outcomes from 22 transplants, with no early deaths.⁶ Many of these lungs were from DCD donors. In a larger cohort, survival remained good but there was a significant reduction in PGD, compared with untreated transplants done in the same era.

But the real strength of EVLP may be in reconditioning the damaged lung, which is taken outside the inflammatory milieu of the donor. The perfusate contains no complement, white cells or platelets, and is hyperosmolar. It draws excess interstitial fluid out of the lung, and dilutes out pro-inflammatory cytokines. High-dose steroids and antibiotics complete a setting for lung recovery. The original Swedish group first showed that EVLP allowed safe use of previously unacceptable lungs,⁷ and now clinicians at a number of UK centres have shown the same. These efforts have culminated in an National Institute for Health Research (NIHR) funded multicentre study (DEVELOP-UK), starting in Spring 2012 and running for 3 years, which hopes to show that EVLP can give equally good outcomes from initially unacceptable lungs.

If EVLP is successful, there is a real prospect of doubling the number of lung transplants over the next 3 years. Moreover, if the suggestion of less damage, and less PGD, is borne out, this will have the added benefit of longer and better survival for the increased numbers of fortunate recipients

 

 References:

1.         Meachery, G., et al., Outcomes of lung transplantation for cystic fibrosis in a large UK cohort. Thorax, 2008. 63(8): p. 725-31.

2.         Robertson, A.G.N., et al., Lung transplantation, gastroesophageal reflux, and fundoplication. Annals of Thoracic Surgery, 2010. 89(2): p. 653-60.

3.         Mascia, L., et al., Effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial. JAMA. 304(23): p. 2620-7.

4.         Dark, J.H. and J.H. Dark, Lung transplantation from the non-heart beating donor. Transplantation, 2008. 86(2): p. 200-1.

5.         Erasmus, M.E., et al., Lung transplantation from nonheparinized category III non-heart-beating donors. A single-centre report. Transplantation. 89(4): p. 452-7.

6.         Cypel, M., et al., Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med, 2011. 364(15): p. 1431-40.

7.         Ingemansson, R., et al., Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Annals of Thoracic Surgery, 2009. 87(1): p. 255-60.