Eur Respir J REVIEW 1990, 3 , 594-605 Transplantation of the lung T. Higenbottam, B.A. Otulana, J. Wallwork Transplantation of the lung. T . Higenbottam, BA. Otulana, J. Wallwork. Dept of Respiratory Physiology, Papworth Hospital, ABSTRACT: The Introduction of cyclosporlne as a highly effective Papwonh Everard, Cambridge CB3 8RE, UK. Immunosuppressive agent and the development of new techniques for heart­ lung and lung transplantation have led to a new treatment for a wide Correspondence: Dr T. Higenbottam, Dept of range of fatal cardiopulmonary diseases. Indications for surgery are now Respiratory Physiology, Papwonh Hospital, Papwonh Everard, Cambridge CB3 8RE, UK. becoming clear, together with major contra-indications. Suppurative lung disease, such as cystic fibrosis, can be effectively treated by heart-lung Keywords: Lung transplantation, heart-lung transplan­ transplant (HLT). A whole new field or pulmonary medJcine is emerging tation, lung rejection, obliterative bronchiolitis. to provide the physiological monitoring and diagnostic techniques for major complications such as opportunistic lung Infection and pulmonary Received: August, 1989; accepted after revision rejection. Obllteratlve bronchiolitis, a consequence of frequent and severe November 30, 1989. rejection, stlU provides a major challenge to the immunological scientist and respiratory physician. Lung transplantation, by disrupting the vascu­ lar supply and innervation of the lung, Is raising major questions about the generally accepted beliefs of regulation of breathing and pulmonary mechanics. Finally, as the survival rate improves beyond the current SO% at 3 yrs, lung transplantation will perhaps present further challenges to our understanding of the pathogenesls of various diseases such as asthma and cystic fibrosis. Eur Respir 1., 1990, 3, 594-605. Tbe surgical techniques long-tenn survival. The healing of the tracheal anasto­ mosis, with the "en bloc" technique, is aided by With the clinical success of renal and cardiac collateral blood supply arising from the mcdiatinum, transplantation tremendous interest developed in the principally the coronary arteries which supply the lower possibility of lung and heart-lung transplantation for trachea and carina [9]. end-stage cardiopulmonary and lung disease. Early Widespread use of HLT is limited by availability of animal studies confirmed the technical feasibility of lung suitable donors, particularly as cardiac transplantation is transplantation, but concern remained about long-tenn so successful [10]. Single lung transplantation offers a survival, particularly in the absence of vagal innervation solution by enabling lungs and heart to be used for of the lung [1]. Non-primate mammals appear unable to separate recipients. The introduction of the "omental sustain ventilation without pulmonary vagal innervation wrap" [11) mobilizing the omentum and wrapping it but, fortunately, primates [2] including man sustain around the bronchial anastomosis has contributed to nonnal ventilation despite loss of pulmonary vagal clinically successful single lung transplantation [12]. innervation [3]. Double lung transplantation, without the heart has also Early experience of clinical lung transplantation was been described [13] but tracheal anastomosis healing is not promising, long-tenn survivors being rare [4]. One poorer than in HLT presumably because of the loss of of the main problems encountered by early workers mediastinal collaterals. Alternatively bilateral bronchial involved the healing of the airway anastomosis [5]. Two anastomosis with "omental wraps" may offer a solution scientific developments, however, provided a solution. to enable double lung transplantation [14]. But as HLT In 1976, BoREL et al. discovered the powerful appears so successful, to enhance the availability of donor immunosuppressive, cyclosporine (previously called organs the "domino" operation has been devised where cyclosporin A) which inhibits T lymphocyte helper cells, the heart of the HLT recipient is donated to another probably by binding to a specific protein receptor, called cardiac recipient. cyclophilin [7]. High dose steroids could be avoided, particularly during the early post-operative period, by use of cyclosporine, with clear benefits to wound heal­ Medical after care ing. Using an earlier report of a similar surgical tech­ nique, REITZ et al. in Stanford [8] developed the "en Early experience of lung transplantation identified two bloc" heart-lung transplant (HL1) operation in a primate major problems in aftercare. The first was a high model in combination with cyclosporine to achieve incidence of primary graft failure, so called TRANSPLANTATION OF THE LUNG 595 post-implantation syndrome which closely resembles adult Table 1. - Causes of early surgical death in eight respiratory distress syndrome [15]. The second was the heart-lung transplant (HLT) recipients in the immediate inability to detect graft rejection and distinguish rejec­ post-operative period tion from pulmonary infection; lung rejection in a chronic Number of patients form contributing to long-term graft failure [16]. Cause of death Cerebrovascular event 2 Tracheal dehiscence 1 Preservation of the donor lung Inflated/ruptured aorta 1 Small bowel infarction/SLE 1 It is essential that after lung transplantation, the new ARDS/hepatic dysfunction 1 graft function immediately. There is no equivalent to Early graft failure 1 haemodialysis, which is used in renal transplantation to ensure the patient's survival until the graft begins to Total 7 out of 61 operations function. During the donor operation and with subse­ ARDS: adult respiratory distress syndrome. quent transportation to the recipient the lungs experience prolonged ischaemia. To reduce ischaemic injury solid organs are cooled [17]. Colloidal solutions seem beuer vehicles to cool the lungs than crystaloid solutions [18]. Table 2. - Criteria for donor selection Also, it is probably better to keep the lungs inflated than 1. Age below 40 yrs. deflated [19] in preserving function. Using these prin­ 2. No major thoracic trauma. ciples the early HL T surgery involved transporting the 3. No past history of pulmonary disease, including asthma. donor to the recipient hospital, the donor and recipient 4. A short period of ventilation. operations being performed in adjoining operating 5. No systemic or pulmonary infections. theatres to reduce to a minimum the ischaemic time. 6. Normal chest X-ray. Obvious practical and ethical problems ensued from 7. Normal lung compliance with peak inspiratory pressure moving donors, which limited availability, a method for <20 nunHg, tidal volume of <15 ml·kg·1 and respiratory 1 long-term preservation was therefore needed. rate 10-14 br·min· • 8. Normal gas exchange, arterial oxygen tension (Pao2) ) 300 • <15 kPa with fractional inspiratory oxygen (Fto2 30%. 9. Inotropic requirement <10 )J.g·kg"1·min·1 of dopamine or dobutamine. 10. Normal electrocardiogram (ECG). 250 vascular bed, before infusion of a single flush colloidal 200 based preservation solution [21, 22). This method • achieves ischaemic times up to 5.5 h and excellent <>I 0 :I: E immediate graft function (fig. 1}. Only one primary graft E failure occurred in 61 HLT patients where most were 150 • 8c extubated within 24 h of surgery (table 1). At present the ~ 0 main limit to the ischaemic time in HLT is probably the 0 '0= inability to preserve cardiac function. N 0 0 0... 100· 0 No matter how effective the long-term preservation c( system, careful selection of the donor organs is impor­ • tant (table 2) to lessen the risks of using injured or 50· damaged lungs and to avoid obviously infected organs. 0 Diagnosis of lung rejection After Pre- One week bypass extubation postoperatlvely Lung rejection was a major problem in the early ) Fig. I. - Alveolar·atterial oxygen gradient (A-ao2 for near and distant experience of transplantation. Repeated untreated acute procurement groups at various times post-operatively. rejection is now thought to have contributed to the dis­ abling and fatal airways obstruction seen in up to 50% Recently a number of methods have been described to of HLT patients [20, 23). With HLT it had been thought extend ischaemic times to enable procurement of organs that endomyocardial biopsy (EMB), a method established from distant hospitals. One such method involves a to diagnose rejection in cardiac transplantation [24], could mechanical system which perfuses the heat-lung block be used to monitor rejection. However, both experimen­ during transportation [20]. Another was using tal [25] and clinical [26) studies suggest that the lungs cardiopulmonary bypass to cool the lungs before har­ undergo rejection before the heart. Indeed we have now vesting. Perhaps the simplest method uses intravenous abandoned the use of EMB in HLT patients as cardiac prostacyclin (PGI2) to vasodilate the donor's pulmonary rejection is rare if the lung rejection is controlled [27]. 596 T. HIGENBOTTAM, B.A. OTID..ANA, J. WALLWORK Additionally, HLT patients commonly experience pul­ A monary infections [20]; the same is true for single lung transplant patients [12]. Transbronchial lung biopsy (TBB) through a 140 FEV1 fibreoptic bronchoscope provides a sensitive means for diagnosing lung rejection [28] anq enables distinction 120 from pulmonary infection [29]. The technique has now "0 been extended to child HLT patients [30]. G) With a clear hiStological diagnosis it has proved pos­ ..Q. 100 sibte to demonstrate the clinical featw:~