92 Heart and lung transplantation

FURTHER READING
Future perspectives
HEART TRANSPLANTATION
Heart retrieval
Heart–lung transplantation
Introduction
LUNG TRANSPLANTATION
Learning objectives
Lung retrieval
Operative technique
Outcomes and complications
Recipient selection
SUMMARY
Ventricular assist devices
preservation

Future perspectives

Contemporary immunosuppressive therapies and modern surgical and perioperative techniques have all contributed to improved outcomes. The principal innovations being investi gated for the future are aimed at increasing donor availability and improving the long-term survival. Xenotransplantation has been extensively investigated with the use of transgenic pig hearts. In 1964, Hardy perfor a xenotransplant using a chimpanzee heart that beat for 90 minutes before failing, and in 1984 infant Ste phanie Fae Beau clair (often referred to as Baby Fae) famously lived for 21 days after receiving a baboon heart. Gene-editing techniques that allow modiﬁcation of antigen expression are among the big gest technological breakthroughs to support the resurgence of xenotransplanta tion. Knockout pigs that lack swine leukocyte antigens to reduce organ immunogenicity ha ve led to pig to-primate allograft survival of up to 945 days. Despite the technical and scientiﬁc challenges the ﬁrst contemporary pig- to-human transplant was undertaken in 2022 at the University of Maryland, USA, with good early clinical xenograft func tion using a pig heart with 10 genetic modiﬁcations, including four knockouts (thr ee responsible for rapid antibody-mediated rejection of pig organ and one to prevent excessiv e growth) and six human genes added to increase the likelihood of accep tance. Rejection in the medium and long term and the hazard of infection transmission with porcine retroviruses remain of concern. The problems faced by xenotransplantation could be overcome b y organ engineering. Decellularised extracellular matrix sca ﬀ olds of hearts can be created by removing cellular tissue then re populating with autologous cardiac cells. Auto matic contractility has been demonstrated. In addition to ﬁnding new sources of donor organs, improve ment of long-term survival remains a priority . New agents to - more favourable side-e ﬀ ect proﬁle remain under investigation. The induction of tolerance of the recipient immune system to donor antigens has promise and T -cell co-stimulation block - ade, mixed chimerism (recipient bone marrow engraftment with donor bone marrow cells) and regulatory T-cell infusions are being studied. Personalisation of current immunosuppres - sants to individual patients may allow for adjustments based on molecular diagnostic techniques to increase e ﬃ cacy and - reduce side e ﬀ ects. Future perspectives

Bioengineered artiﬁcial lung technology using recipient cells grown onto a decellularised lung sca ﬀ old is under development and will avoid an immune response; however, it remains a long way from clinical reality . Success would permit lung transplan tation without the need for immunosuppression, waiting lists or rejection. Artiﬁcial lungs, mimicking the success of V ADs in heart transplantation, remain elusive. The physical volume of mem brane oxygenators is too great f or implantation within the thorax and devices are not durable, lasting weeks rather than months or years . Membranes are thrombogenic and high levels of anticoagulation would be required.

HEART TRANSPLANTATION

The incidence of heart failure is increasing as the population ages and coronary artery disease, hypertension and obesity rise. Current medical therapy , including resynchronisation pacemakers and implantable deﬁbrillators, is e ﬀ ective in improving symptoms and survival but many will develop end-stage disease for which heart transplantation remains the gold standard surgical treatment. Experimental procedures by Demikhov in the 1940s and the xenotransplantation of a chimpanzee heart into a patient with intracardiac thrombus by Hardy in 1964 led Lower and Shumway at Stanf ord University , CA, USA, to demonstrate that the circulation could be maintained entirely by an orthotopically transplanted heart. The ﬁrst clinical heart transplant was undertaken in 1967 by the South African Christian Barnard, but mortality remained very high until the advent of modern immunosuppressants. Heterotopic heart transplantation, in which a donor heart is transplanted as a biological biventricular assist with the native heart remaining in place, was ﬁrst used clinically in 1974 but is now seldom used as long-term survival is poor.

Heart retrieval

After exposing the heart by median sternotomy and opening - the pericardium the organ is thoroughly inspected for contrac - tility and coronary artery disease. Heparin is administered (300 /uni00A0 U/kg) and a cannula placed into the aorta. The venae cavae are then occluded, the aorta cross-clamped and cardio - plegia administered to arrest and cool the heart. The inferior vena cava (IV C) is vented. When the lungs are retrieved the pulmonary artery will also have been cannulated and the left atrial appendage incised. Cardiectom y is then carried out by dividing the superior vena cava (SVC), removing the cross-clamp and dividing the aorta and pulmonar y artery at the bifurcation. The inferior vena cav al incision is completed and the heart lifted to expose the inferior wall of the left atrium, which is then circumfer - entially incised to explant the heart. The interatrial septum is inspected to rule out a patent foramen ovale and all valves are carefully examined. The heart is then placed in a bag ﬁlled with cardio plegia solution at 4°C. Two additional sterile bags are wrapped around it. T hese bags are then placed in a sterile container and then in a cooler for transport.

Figure 92.3 An organ care system that allows retrieved hearts to be perfused with warm oxygenated blood and remain beating during transportation to the recipient hospital. Devices can shorten isch aemic time and may be bene /f_i cial in higher risk patients. They have facilitated highly successful donor circulatory arrest heart donation to expand the donor pool.

Heart–lung transplantation

Combined heart–lung transplantation is an excellent treat ment for PAH ( Figure 92.10 ). However resolution of right ventricular dysfunction has been observed consistently after bilateral lung transplantation, making it the favoured option in the vast majority of patients, Cur rently , the main indication is in congenital heart disease with pulmonary hypertension. Early post-transplant survival remains lower than after lung transplantation. After a peak of activity in the late 1980s, the number of procedures has steadily declined to less than 100 /uni00A0 per annum. Organ allocation systems are weighted towards directing hearts and lungs separately to urgently listed patients, making combined heart–lung donor blocks a rarity for these patients.

Introduction

No content extracted automatically.

LUNG TRANSPLANTATION

Pulmonary transplantation has made signiﬁcant advances since the ﬁrst human lung transplant performed by James Hardy in 1963 in Mississippi, USA. Mortality and morbidity remain high, in part because lungs remain exposed to the environment through the airway . - For patients with end-stage pulmonary disease, lung trans - plantation can signiﬁcantly improve both survival and quality of life. Approximately 80% of lung transplants are bilateral, with single-lung transplants and living related lobar transplants undertaken less often. Long-term outcomes for all recipient pathologies ar e superior with bilateral lung transplantation. Single-lung transplantation cannot be used in diseases where infection may remain in the other lung, such as in cystic ﬁbrosis (CF) or bronchiectasis. -

Learning objectives

To recognise and understand: The indications and contraindications to transplantation of â€¢ the heart and lungs The selection of recipients â€¢

Lung retrieval

Flexible bronchoscopy is ﬁrst performed to clear mucopuru - lent secretions or aspiration. After median sternotomy and exposure of the lungs in each pleural space, detailed inspection is carried out for masses, consolidation or contusion. Uniform atelectasis. Lung compliance is also assessed by observing lung deﬂation when disconnected from the ventilator. Heparin is administered and the main pulmonary artery cannulated. Prostaglandin E (500 /uni00A0/uni03BC g) is then injected to induce pulmonary vasodilatation and 3 litres of a cold pulmoplegia preservative infusion is initiated. The left a trial appendage is incised to vent the e ﬄ uent while the lungs are also topically cooled with saline. Lung ventilation continues during ﬂushing to improve ﬂuid distribution and prevent atelectasis. The pulmonary artery is then divided proximal to the bifurcation and the left atrium is incised to create a cu ﬀ of left atrium on each side, into which the two pulmonary veins drain. Division of the pulmonary ligament on each side allo the lungs to be removed after inﬂating them to 25 /uni00A0 mmHg and stapling the trachea, the lungs remaining inﬂated for transpor tation. A 500-mL retrograde pulmoplegia infusion is carried out into each pulmonary vein to augment preservation and ﬂush out clots from the vasculatur e. The lungs are then placed into a bag containing pulmo plegia and double-bagged for transport within an ice-packed cooler. Lungs are more resistant to warm and cold ischaemic times and safe transplantation can be undertaken with preservation times of 6–12 hours. As in heart transplantation the use of DCD donors has expanded the donor pool. After the declara tion of death the lungs are rapidly retrieved. Lungs are resistant to the e ﬀ ects of warm ischaemia much more so than the heart and outcomes are equal to those obtained with DBD donors. The avoidance of the catecholamine storm and associated inﬂammation asso ciated with brain death may be particularly advantageous in these cases. The technique for DCD lung retrieval is somewhat di ﬀ er ent. Five minutes after the declaration of death, br onchoscopy is performed and the lungs inﬂated. After rapid chest entry the pulmonary artery is quickly cannulated, the left atrial quickly inspected for abnormalities and topical hypothermia is accomplished with ice slush to limit the warm ischaemic time. Most donors involve controlled withdrawal of treatment (Maastricht 3) but uncontrolled DCD (Maastricht 2) dona - tion where failed resuscitation from unexpected cardiac arrest with a declaration of death is f ollowed by heparinisation, the in situ cooling of the lungs and insertion of chest drains with consent for donation and organ retrieval has been shown to be e ﬃ cacious in Spain. The use of ex vivo lung perfusion (EVLP) is recommended to allow for assessment. Ex vivo lung perfusion This technique involves placing donor lungs into a machine ws at the recipient centre; the lungs are ventilated and perfused with an electrolyte and protein solution for 2–4 hours, some - - times longer. This permits the reconditioning and evaluation of lungs that may not appear to be useable for transplantation in the ﬁrst instance. Treatments may be administered that can optimise graft function, suc h as antibiotics, steroids and immunomodulatory drugs, and biomarkers for poor outcomes - can be detected. EVLP may be used for logistic reasons to reduce ischaemic time and in the future it may permit ex vivo therapeutic interventions such as gene therapy . By using perfusates with an optimised colloid osmotic pressure, pulmonary oedema can be reduced, thereby improving gas exchange. The lungs can be monitored on the device for the development of changes in compliance, airway pressure, pulmonary vascular resistance and perfusate oxygenation. Bronchoscopy can be performed to resolve areas of atelectasis ( Figures 92.6 and 92.7 ). - -

Figure 92.6 Ex vivo lung perfusion. The lungs have been explanted from the donor but may be borderline for acceptance for trans plantation. Perfusion, bronchoscopy and ventilation in the system can recondition lungs to a useable state to permit the transplant to proceed. Ventilator Temperature probe in the open left atrium Pressure measurement PA LA Reservoir Leukocyte /f_i lter Haemoconcentrator O , N , CO 2 2 2 Pump Oxygenator Temperature probe HCU

Figure 92.7 Schematic of a typical ex vivo lung perfusion circuit. HCU, heater–cooler unit; LA, left atrium; PA, pulmonary artery.

With this technique, lungs can be evaluated for function and quality between donation and transplantation with 35–97% of initially unacceptable lungs being used successfully with 5-year mortality rates equivalent to those of conventional transplan tation, although some studies have suggested an increase in postoperative ECMO requirements and longer intensive care unit stays. A di ﬀ erent EVLP system that involves a portable organ preserv ation system taken to the donor hospital rather than the recipient hospital has also been shown to have favourable safety and e ﬃ cacy . Trials have been completed in which EVLP was used in standar d criteria donors to assess whether this would lead to improved outcomes but no beneﬁt was demonstrated.

Figure 92.8 The clamshell thoracotomy commonly used for bilateral lung transplantation. Bilateral anterior thoracotomies through the fourth or /f_i fth intercostal space are connected by division of the ster num. This facilitates excellent visualisation of the thorax

Operative technique

Coordination between the retrieval team and the implanting team is of paramount importance to minimise ischaemic time and the duration of cardiopulmonary bypass. A median sternotomy incision is performed and the aorta, SVC and IVC are encircled. After heparin administration the to establish cardiopulmonary bypass. Blood is drained from the ca vae into a reservoir, then oxygenated, cooled to 32°C and returned via a roller pump to the ascending aorta to perfuse the bod y while the heart is excised and the transplant performed ( Figure 92.4 ). Carbon dioxide is insu ﬄ ated into the pericardial cavity to reduce the risk of air embolism. When the donor heart arrives in the operating theatre, the recipient aorta is cross-clamped and the heart excised by dividing the SVC, IVC, aorta and pulmonary artery . The left atrium is incised, leaving a cu ﬀ of atrium into which the f our pulmonary veins drain. After administering a dose of cardioplegia to the donor heart, the left atrial cu ﬀ is anastomosed, followed by the pulmo - nary artery , aorta and both cavae. Donor and recipient vessels are trimmed to obtain a perfect match in ter ms of length and width. A vent is placed in the ascending aorta for de-airing and the cross-clamp is removed, allowing reperfusion of the heart ( Figure 92.5 ). Steroids are usually administered to reduce rejection. Sinus rh ythm is usually restored but temporary pacing wires are sutured to the heart for heart rate control. After a period of reperfusion (20 minutes for each hour of ischaemic time) to allow myocardial r ecovery , the new heart can be separated from cardiopulmonary bypass gradually , until it has taken over the circulation. Nitric oxide is useful at this stage to reduce pulmonary vascular resistance and protect the right ventricle from dysfunction. Isoprenaline is commonly infused. A transoesophageal echocardiogram can help to assess biventricular function and valvular competence.

Oxygenator Right atrium Reservoir Figure 92.4 Cardiopulmonary bypass is used in heart transplantation and sometimes in lung transplantation. Blood is drained from cannulae in the superior and inferior venae cavae to a reservoir, then oxygenated in a membrane oxygenator before return to the ascending aorta via a roller or centrifugal pump. The patient can have their circulation maintained with oxygenated blood while the heart or lungs are explanted during transplantation.

Operative technique

The decision as to whether to use extracorporeal support during the transplant in the form of cardiopulmonary bypass or ECMO during bilateral lung transplantation varies with institutional experience, intraoperative stability and patient selection. Cannulation can be achieved either within the thorax or peripherally via the femoral vessels. A clamshell thoracotomy incision ( Figure 92.8 ) through the fourth or ﬁfth intercostal space is often favoured with divi sion of the sternum, but the procedure may also be performed using separate bila teral sternum-sparing anterior thoracoto mies or via median sternotomy . After opening both pleurae the pericardium is opened in preparation for central cannulation and to aid with hilar dis section and r etraction of the heart. There are often signiﬁcant adhesions in the pleural spaces that need dissection, although care not to injure the phrenic or vagus nerv es should be exer cised. If an elective decision is made for cardiopulmonary bypass or ECMO, heparin is administered and aortic/femoral artery Victor Satinsky , 1912–1997, American cardiovascular surgeon and co-creator of coronary bypass sur right atrial (direct or via the femoral vein) cannulation for venous drainage. Extracorporeal support is generally avoided where possible owing to increased b leeding and an association with ischaemia–reperfusion injury . After releasing the inferior pulmonary ligament, hilar dis - section is carried out and pneumonectomy performed by divi - sion of the bronchus, pulmonary artery and both pulmonary veins. A large Satinsky clamp is placed across the left atrium and the individual pulmonary veins are opened and connected, creating a recipient cu ﬀ for anastomosis. Recipient lung bronchial secr etions are sent for microbiol - ogy and the hilum is prepared by circumferentially opening the pericardium to mobilise the left atrium and pulmonary artery . Mediastinal lymph nodes may need excision to facilitate the transplant. Bronchial arteries are ligated to prevent signiﬁcant b leeding. Denudation of the recipient bronchus should be avoided to limit local ischaemia at the site of the anastomosis. The pleural space is then liberally irrigated with antibiotic or aseptic solutions. The donor lungs are prepared for implantation by obtain - ing bronchial cultures for microbiology and dissecting the bronchus, pulmonary arteries and the left atrial cu ﬀ , into which the two pulmonary veins drain. Importantly the donor bronchus should be cut short just one or two rings from the - bifurcation into the upper and lo wer lobe bronchi to minimise ischaemia at the anastomosis. The implantation is then conducted by sequentially cre - ating anastomoses between the bronchus, the left atrial cu ﬀ of the donor lung and the left atrium of the recipient and the pulmonary artery ( Figure 92.9 ). Prior to reperfusion, 500 /uni00A0 mg of intravenous methylprednisolone is administer ed. The pulmonary artery clamp is removed slowly to lessen reperfusion injury and blood is permitted to escape from the left atrial suture line to de-air the vasculature before the left atrial clamp is opened. After a period of ventilation on a lo w inspired oxygen con - centration to reduce oxygen free radical release, the patient is ventilated and weaned from cardiopulmonary bypass or - - - - gery .

Bronchus Recipient left atrium Pulmonary artery Donor pulmonary vein Figure 92.9 Hilum of the lung during lung transplantation. A left atrial cuff is fashioned into which the donor pulmonary veins drain. This is anastomosed to the left atrium of the recipient. The bronchus has been anastomosed already and the pulmonary artery is to be con

nected next.

phy is used to check de-airing and the patency of the vascular anastomoses. There has been a growing trend in the use of living related lobar lung transplantation for small recipients, especially in restrictive lung disease with low intrathoracic lung volume with two relatives each undergoing lower lobectomy . Results in a limited number of centres have been good but must be balanced against the risk of complications or death in the two donors. Alternatively larger donor lungs can be reduced in size through multiple wedge resections and right middle lobectomy . With this technique, variable outcomes have been reported when using o versized donor lungs with donor–recipient size mismatch.

Outcomes and complications

Survival has dramatically improved with advances in immuno - suppression and perioperative care, with 1-year post-transplant survival of over 90% and a median post-transplant survival of

Pump Aorta Pulmonary artery Right ventricle

approximately 12 years anticipated. Early mortality is 5–10% at 30 days but often higher in those who have a V AD implanted as the device must be explanted with the recipient’s heart, increasing the complexity of surgery owing to adhesions and vasoplegia from long-term non-pulsatile ﬂow or infection often being encountered. After surgery most patients do not require rehospitalisation and functional status is good, with many returning to work and having a greatly improved health-related quality of life. Denerv ation of the heart is an unavoidable consequence of transplantation but, despite this, baseline cardiac function is preserved and increases in cardiac output are mediated by cir culating catecholamines and stretch receptors responding to increased venous return with exercise. Early after transplantation, the main causes of mortality include primar y graft dysfunction, rejection and infection. Long-term survival is dictated by the development of chronic allograft vasculopathy (CA V) and immunosuppression-related malignancy , diabetes, infection and renal dysfunction. Primary graft dysfunction occurs soon after implantation in around 10% of cases and is the leading cause of death. Low cardiac output and uni- or biventricular failure secondary to ischaemia–reperfusion injury occurs and is associated with older donor or recipient age, female-to-male donation, pro longed ischaemic time (>240 minutes) and donor-to-recipient size mismatch. Escalating inotropic support is needed, some times culminating in the institution of ECMO for circulatory support until the reco very of heart function. Isolated acute right ventricular failure may occur second ary to prolonged ischaemic time, elevated pulmonar y vascular resistance, volume overload or donor size mismatch. The use of inotropes and nitric oxide and the optimisation of volume and mechanical support ma y be required. Three types of rejection can occur after heart transplan - tation: hyperacute rejection, acute cellular rejection and antibody-mediated rejection. Hyperacute rejection occurs intraoperatively immediately after reperfusion. Cross-matching of blood type and panel reactive antibodies has r endered this very unlikely . Lifelong immunosuppression is required, balancing pre - vention of rejection but avoiding the adverse e ﬀ ects of malig - nancy , infection, renal dysfunction, hypertension, diabetes and hyperlipidaemia. Most patients are prescribed triple therapy , consisting of a calcineurin inhibitor (e.g. ciclosporin, tacroli - - mus), an antimetabolite (e.g. azathioprine) and a tapering dose of ster oids. Induction therapy with antithymocyte globulin or interleukin-2 receptor antagonists (basiliximab) is sometimes used but this may increase the risk of infection and malignancy with no survival beneﬁt. The risk of acute r ejection is highest in the ﬁrst 6 months and a regime of routine surveillance cardiac biopsies obtained from the right ventricle via a bioptome inserted through the internal jugular vein are carried out. Alternatives to biopsy hav e been explored, especially the modalities of cardiac imag - ing, but they have been associated with low accuracy . Gene expression proﬁling of blood mononuclear cells is under inves - - tigation and may be promising in the future . Free DNA of donor origin in the recipient’s blood has also been tested as a - means to predict rejection in the transplanted heart. Acute cellular rejection is a T -cell reaction to the donor’s HLA molecules that occurs in 20–40% of patients, most com - - monly during the ﬁrst 12 months. It is classiﬁed based on the severity of lymphocytic inﬁltrates and myocyte damage and is treated with high-dose corticosteroids . With modern immuno - suppression and the low risk of la te cellular rejection, biopsies are often ceased after 3 years.

Brachiocephalic Left common carotid artery trunk Left subclavian artery Superior vena cava Ascending aorta Right superior pulmonary vein Right inferior pulmonary vein Left atrium Inferior vena cava Figure 92.5 Cardiac transplantation. (a) A left atrial cuff is fashioned, into which the four pulmonary veins drain. This is anastomosed to a cuff of left atrium on the donor heart followed by anastomosis of the pulmonary artery, aorta and both venae cavae to complete the implant Arch of aorta Superior vena cava Pulmonary artery trunk Left atrium Right atrium Inferior vena cava (b) .

and has a mortality rate of 8%. Donor antigens and recip ient antibodies form an antigen–antibody membrane attack complex that leads to endothelial injury . The diagnosis of antibody-mediated rejection is conﬁrmed by the presence of circulating donor-speciﬁc antibodies (DSAs) with evidence of complement activ ation. This is treated with intravenous immunoglobulin, plasmapheresis, antilymphocyte antibodies and high-dose steroids. CA V is a frequent long-term complication of heart trans plantation and the leading cause of late mortality . It has an incidence of 30% at 5 years with a complex pathogenesis involving immunological factors and ischaemia–reperfusion all implicated. Di ﬀ use thickening of coronar y arterial intima occurs, often a ﬀ ecting the entire length of the epicardial vessels and typically extending to the microvasculature. As the heart is denervated recipients do not experience ischaemic chest pain. By the time the patient presents with declining left ventricular function and heart failure, the prognosis is poor. CA V surveil lance by serial coronary angiography often combined with intravascular ultrasound can reliably detect intimal changes early to allow for treatment modiﬁcation or consideration of retransplantation. Outcomes and complications

Current median survival after pulmonary transplantation is 6.2 years. In recipients who survive the ﬁrst year the median survival is 8.3 years and this is associated with a signiﬁcant improvement in quality of life. The main cause of postoperative mortality is primary graft dysfunction in which ﬂorid pulmonary oedema occurs with di ﬀ use alveolar damage resulting from ischaemia–r eperfusion injury . In survivors this is also associated with later dysfunc tion of the graft in the form of bronchiolitis obliterans syn drome (BOS). The pathogenesis is highly complex and involves acute-phase cytokines that are involved in inﬂammation that are upregulated or augmented in response to ischaemia or reperfusion and donor-speciﬁc characteristics suc h as infec tion, transfusion, barotrauma or smoking. Summary box 92.6 Complications of lung transplantation /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Summary box 92.7 Immunosuppression after heart and/or lung transplan tation /uni25CF /uni25CF /uni25CF /uni25CF lation, nitric oxide to improve ventilation–perfusion mismatch and diuresis. Support with ECMO is highly beneﬁcial to allow for lung protective ventilation with eventual weaning when the lung injury recover s. Infections are the second highest cause of mortality within 30 days. Most centres use broad-spectrum antibiotics in the postoperative period based on bronchoalveolar lavage speci - mens from both the donor and recipient lungs. Using donor lungs from hepatitis B core-positive donors is feasible with a low risk of transmission. Rejection commonly occurs after lung transplantation. Immunosuppression is used postoperatively to pr event acute rejection as well as CLAD by inhibiting T- and B-cell proliferation and activation. Agents similar to those used after heart transplantation ar e commonly utilised but generally greater immunosuppression is needed compared with other organs because of the increased susceptibility of the lungs to rejection, and this signiﬁcantly increases the risks of drug toxicity such as renal failure, diabetes and hypertension. Induction therapy may be given as in heart transplants but is not universally applied and side e ﬀ ects such as major infection and malignancies limit its use despite evidence of a survival beneﬁt. Acute cellular rejection occurs in around 30% of patients - in the ﬁrst year and is characterised by an acute decline in - pulmonary graft function without any other cause. Diagnosis is conﬁrmed histologically using scheduled transbronchial biop - sies and is based on the presence of perivascular and interstitial mononuclear cell inﬁltrates. Pulsed high-dose steroid therapy - is the mainstay of treatment with modiﬁed or augmented immunosuppression in resistant cases. Antibody-mediated rejection is a separate entity in which DSAs directed towards donor HLA are present with neutro - phil margination, arteritis and evidence of complement activa - tion (C4d) present on histolog y . Treatment strategies focus on using plasmapheresis to deplete circulating DSAs, intravenous immunoglobulin and rituximab. Despite this a poor outcome is expected with a 1-year survival of less than 50%. CLAD (whic h includes BOS) limits long-term survival after lung transplantation and has a prevalence of 50% at 5 years. It leads to a signiﬁcant fall in lung function and treatment options ar e limited but may include extracorporeal photopheresis combined with augmented immunosuppressive regimens and total lymphoid irradiation. Pirfenidone is being investigated as a possible option. In advanced CLAD, retransplantation can be considered. Gastro-oesophageal reﬂux disease is very common after pulmonary transplantation and has a strong association with the development of CLAD. Intraoperative vagal nerve injury , loss of cough reﬂex, impaired mucociliary clearance and immunosuppression-related gastroparesis may all be impli - - cated. Early fundoplication has been suggested as an option. The bronchial anastomosis is a common site of compli - cations with dehiscence occurring from local ischaemia or infection and stenosis occurring longer term in 5% of cases. Reoperation to cover a defect with an intercostal muscle ﬂap or endobronchial stent insertion for narrowed anastomoses is e ﬀ ective.

Primary graft dysfunction Bleeding Parenchymal and pleural infection Bronchial anastomotic dehiscence or stenosis Vascular anastomotic stenosis or kinking Rejection – acute or chronic (chronic lung allograft dysfunction [CLAD]) Infection – bacterial, viral or fungal – donor or recipient acquired Phrenic nerve palsy Gastro-oesophageal re /f_l ux Induction (if used) Antithymocyte globulin/interleukin-2 receptor antagonists (basiliximab) Maintenance Ciclosporin, azathioprine, methylprednisolone

Single Double Figure 92.10 Types of lung transplant. Heart–lung combined transplantation is now rarely performed and is reserved mainly for congenital heart disease associated with pulmonary hypertension. Bilateral lung transplantation is the commonest option and accounts for 80% of transplants performed. Single-lung transplantation can be used in cases where retention of the other lung will not pose a risk from infection, such as /f_i brotic lung disease or emphysema. Using this option in cystic /f_i brosis, for example, would be contraindicated. Single-lung transplantation is associated with inferior survival. Lobar transplantation is rarely performed but in experienced centres can provide good results in highly selected patients. In living related donation relatives would donate a lower lobe but risk complications.

Recipient selection

The primary indication for transplantation is prolonged advanced heart failure despite optimal medical management, often typiﬁed by repeated admissions or acute deterioration. Vladimir Demikhov , 1916–1998, Russian pioneer of organ transplantation, performed heart and heart–lung transplantation in animals between 1940 and 1950. James Hardy , 1918–2003, performed the world’s ﬁrst lung transplant in 1963, undertook the world’s ﬁrst heart transplant attempt when he transplanted the heart of a chimpanzee into a dying patient in 1964. Richard Lower , 1929–2008, American pioneer of heart transplantation who, with Shumway , developed many of the techniques required, including the use of hypothermia and the orthotopic technique in Stanford, CA, USA. Instrumental in the use of ciclosporin and in developing techniques of myocardial biopsy to monitor rejection. Norman Shumway , 1923–2006, American pioneer of heart transplantation who, with Lower, developed many of the techniques required, including the use of hypothermia and the orthotopic technique in Stanford, CA, USA. Performed his ﬁrst human heart transplant in 1968. Christiaan Barnard , 1922–2001, performed the world’s ﬁrst successful heart transplant in 1967 after studying the techniques used by Lower and Shumway . The decision to transplant must take into account the patient’s ability to withstand surgery and adhere to long-term treatment. The most frequent indications for heart transplantation in adults are dilated and ischaemic cardiomyopathy . An increas - ing number of patients with adult congenital heart disease (ACHD) are now considered but need more complex surgery (abnormal anatomy , previous operations) and ma y have ele - vated pulmonary vascular resistance and immune sensitisation. There are higher early mortality results after transplantation although the long-term outcome in survivors is excellent. Patients should be within the ‘transplant window’, being robust enough to surviv e the operation but their condition and prognosis should warrant the risks involved. As advanced fail - ure can increase risk through the dysfunction of other organs (e.g. cardiorenal syndrome, liver dysfunction) reversible issues that can resolve with the improved cardiac output that trans - plantation will bring must be identiﬁed. Elevated pulmonary vascular r esistance (>5 Wood units and a transpulmonary gradient >15 /uni00A0 mmHg) is associated with an increased risk of right ventricular failure and mortality after heart transplantation; if irrever sible despite vasodilators, this resistance is a contraindication. Age and previous cardiac surgery do not preclude transplantation and neither does diabetes if controlled with an absence of microvascular complications. A body mass index 2 (BMI) >30 /uni00A0 kg/m has been associated with a worse outcome and weight loss is required before listing. Active infection is an absolute contraindication. Patients with chronic infections

Heart and lung donation • The technique for heart and lung transplantation • Early postoperative complications • Long-term outcomes •

and surgical therapy . Malignancy , other than localised non- melanoma skin cancer, precludes transplantation but patients who have achieved sustained remission following cancer therapy may become candidates. The presence of circulating antibodies against the allograft (allosensitisation) owing to pregnancy , blood transfusion, pre vious transplantation and the use of ventricular assist devices (V ADs) is associated with worse outcomes and candidates are likely to ha ve an extended waiting time to ﬁnd a compatible donor. Screening for anti-human leukocyte antigen (HLA) antibodies is routine for all heart transplantation candida Psychosocial factors such as substance abuse (including tobacco, alcohol) is a relative contraindication. Relapse of smoking has been associated with a poor outcome after car diac transplantation. Summary box 92.1 Criteria for heart transplantation β β Summary box 92.2 Factors considered in heart allocation /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Denton Cooley , 1920–2016, American surgeon, performed the ﬁrst implantation of a total artiﬁcial heart and made major contributions to all aspects of cardiac surgery . Michael DeBakey , 1908–2008, American cardiovascular surgeon, undertook the ﬁrst surgery to implant an external ventricular assist device for heart failure and developed a classiﬁcation of aortic dissection. - tes. -

Impaired left ventricular systolic function 2. New York Heart Association III (e.g. patient cannot climb one /f_l ight of stairs without symptoms) 3. Receiving optimal medical therapy (maximum tolerated doses of -adrenergic antagonists, angiotensin-converting enzyme inhibitors, aldosterone antagonists) 4. Resynchronisation pacing or implantable de /f_i brillator device inserted (if indicated) 5. Evidence of a poor prognosis, e.g. a. Exercise testing (O max <12 /uni00A0 mL/kg/min if on -blockade) 2 b. Elevated B-type natriuretic peptide serum levels c. Calculated Seattle Heart Failure score indicating >20% 1-year mortality Biological matching Blood group compatibility Appropriate size matching (accounting for recipient sex and pulmonary hypertension) Need to avoid speci /f_i c donor HLA antigens in sensitised recipients Clinical need Severity of heart failure Prognosis Logistic factors in /f_l uencing ischaemia time Distance of donor from the recipient centre Prior surgery in the recipient (multiple sternotomies) Surgical complexity (e.g. prior VAD, ACHD) Fairness Time on the waiting list Aorta Pulmonary artery Left atrium Right atrium Coronary artery Left ventricle Right ventricle Left ventricular assist device Figure 92.1 Typical implantable left ventricular assist device that takes blood from the apex of the left ventricle and passes it through a rotor to a graft anastomosed to the aorta. A driveline crosses the skin to a controller and battery pack providing electrical power.

Recipient selection

Candidates have advanced lung disease with shortened life expectancy and poor quality of life owing to breathlessness med and oxygen dependency . The most common indications are chronic obstructive pulmonary disease (COPD), CF , pulmo - - nary arterial hypertension (PAH) and interstitial lung disease (ILD). Organ allocation schemes recognise the last as associated with rapid decline and poor prognosis. Their prioritisation has - led to shorter waiting times and a 20–40% reduction in death on the waiting list. The lung allocation score (LAS) is a useful tool to select those most in need of a particular donor lung . - Risks are calculated using a set of 17 patient-related variables, - Summary box 92.4 Pulmonary diseases and type of transplant /uni25CF - /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF - /uni25CF /uni25CF -

Cystic /f_i brosis Bilateral and living related (or cadaveric lobar transplants in small highly selected recipients in experienced centres) Interstitial ( /f_i brotic) lung disease Bilateral or single (but associated with poorer long-term survival) Emphysema/COPD Bilateral or single (but associated with poorer long-term survival) Pulmonary hypertension Bilateral (or rarely combined heart–lung transplantation especially if associated with congenital heart disease)

pulmonary hypertension and the 6-minute walk distance. In deteriorating patients more conventional treatments can be used in some groups before transplant assessment. In COPD endoscopic lung volume reduction is increasingly rec ognised as a treatment option. Transmembrane conductance regulator modulators have improved outcomes for patients with CF with a reduction in exacerbation frequency and an impro vement in quality of life and prognosis. This has resulted in a recent fall in transplantation for CF . In idiopathic pulmonary ﬁbrosis, antiﬁbrotic drugs (e.g. nintedanib, pirfenidone) have slowed the rate of functional decline, but the clinical course remains progressive and unpre dictable. Although age should not be considered a contraindication to transplantation it is associated with comorbid conditions that may need to be taken into account. It is unusual to trans plant patients over 70 years of age. Previous surger y , such as lobectomy , lung volume reduction or pleurodesis, is not a contraindication to lung transplanta tion, although inevitably it makes the transplantation opera tion more challenging with a gr eater risk of bleeding, phrenic nerve injury , chylothorax and renal dysfunction. A pneumo thorax occurring in a waiting-list patient can be managed as r equired as the choice of intervention is unlikely to a ﬀ ect future acceptance. Untreatable major organ dysfunction, sever e athero sclerosis, bleeding diathesis, high or low BMI, severe osteo porosis and chronic infection are all contraindications. In particular, infection with Burkholderia cenocepacia , Burkholderia gladioli and Mycobacterium abscessus can be associated with very poor post-transplant outcomes. For patients infected with hepatitis B and/or C, surgery can occur provided cirrhosis or portal hypertension are absent. Controlled human immuno deﬁciency virus (HIV) disease with undetectable HIV RNA, and compliance with antiretroviral therapy , allows transplan tation to occur. For those with a history of malignancy a low predicted risk of recur rence and a 5-year period of remission are required. With regard to coronary arter y disease, percutaneous coro nary intervention may be undertaken ahead of transplantation or coronary artery bypass grafting when lung transplantation occurs. The degree of coronary artery disease deemed acce able will vary but good results have been achieved. In rapidly deteriorating patients who are otherwise excellent candidates a bridge to lung transplantation may be undertaken using ECMO support. This permits ongoing rehabilitation while /uni00A0 awaiting a suitable organ and is preferable to ventilation, which is usually a contraindication to pulmonary transplan tation as physiotherapy is more di ﬃ cult, deconditioning likely and the onset of pneumonia and barotrauma more common. V enovenous ECMO can be used in patients with severe hypoxia whereas venoarterial ECMO is used for pa tients with both hypoxia and haemodynamic instability or pulmonary hypertension. Instituting ECMO, however, is associated with serious and potentially fatal complications, such as bleeding, infection and thromboembolism. Recent series have shown that outcomes from bridging to transplantation can be similar to those transplanted electively despite being far sicker.

SUMMARY

As the population ages and coronary artery disease, hyperten sion and obesity increase in prevalence the incidence of heart failure continues to rise. Current medical therapy is e ﬀ ective in improving symptoms and survival but man y continue to develop end-stage syndromes. The most critical issue is the growing number of patients on the waiting list and the relatively - static donor pool. V ADs have emerged as a strategy to bridge patients to car diac transplantation if they are deteriorating or as durable destination therapy . However complications such as stroke, pump thrombosis and poorer long-term survival remain a challenge. Cardiac transplantation remains the gold standard for the treatment of end-stage heart failure and is associated with excellent outcomes for patients, but it is limited by chronic rejection and the side e ﬀ ects of immunosuppression. Lung donor availability and increased waiting-list mor - tality are major challenges in pulmonary transplantation, but extended criteria donors can be safely used with good results. ex vivo The use of DCD lungs and organs reconditioned with lung perfusion has further expanded the donor pool, the lat - ter technique showing promise for therapeutic interventions in due course. Bridging patients with ECMO rather than ventilation to lung transplantation is successful for those most in need and new allocation systems have been implemented that have led to decreased waiting list mortality , especially in those with ﬁbrotic - ILD. Overcoming primary graft dysfunction in the early post - operative period and chronic lung allograft dysfunction in the longer term are the main targets of ongoing research to - improve outcomes for lung transplant recipients.

Heart–lung Lobar pulmonary

Ventricular assist devices

V ADs have had a signiﬁcant impact. They may be used as a bridge to transplantation, a bridge to recovery (where the device is explanted if the patient’s cardiac function improves) or as long-term durable destination therapy . The ﬁrst total artiﬁcial heart implant was performed by Cooley in Houston, Texas, USA, in 1969 with the patient sub - sequently undergoing heart transplantation 48 hours later. In 1966, DeBake y utilised a left V AD in a patient unable to wean from cardiopulmonary bypass after valve surgery . Current generation de vices use continuous non-pulsatile ﬂow technology , which permits small device size, has the rotor as the only moving part and uses electrical rather than the more bulky pneumatic power delivery ( Figure 92.1 ). Patients can now remain on device support for years if nec - essary , although complications from anticoagulation (stroke, device thrombosis, gastrointestinal bleeding), right ventricular failure, aortic valve regurgitation and driveline infection are common; hospital readmission is fr equent. Early mortality is akin to heart transplantation but long-term survival is inferior with 50% survival at 5 years. Given the shortage of suitable donor organs, V AD implan - tation is an increasingly common approach for those deterio - rating on the waiting list to gain time for a suitable donor heart to be become available. Future technology improvements are focused on increased biocompatibility , artiﬁcially generated pulsatility and avoidance of drivelines. Among patients admitted in cardiogenic shock, venoarte rial extracorporeal membrane oxygenation (ECMO) can be used to restore perfusion rapidly via the peripheral femoral artery and vein cannulation and permit urgent heart trans planta tion to be carried out within days, although the results are inferior ( Figure 92.2 ). Summary box 92.3 Complications associated with VADs /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF

Ventilator Oxygenator Arterial return line (into body) Venous drainage cannula (out of body) ECMO ECMO pump pump controller Figure 92.2 Extracorporeal membrane oxygenation (ECMO), which can be used for cardiorespiratory support before or after heart and lung transplantation. Blood is drained from the right atrium via the femoral vein, oxygenated and pumped back to the arterial circulation. In a variation where respiratory and not circulatory support is needed (venovenous ECMO) oxygenated blood is returned to the right atrium via the other femoral vein or jugular vein. Anticoagulation Bleeding – gastrointestinal tract, intracerebral, subarachnoid, extradural Thrombosis Pump obstruction Device failure Infection Driveline, systemic sepsis Structural Aortic regurgitation, tricuspid regurgitation Right ventricular failure Higher risks at transplantation Adhesions, infection, vasoplegia

preservation

At the time of heart procurement from brainstem dead (donation after brainstem death [DBD]) donors, the heart must be arrested and explanted prior to transportation. There follows a period of ischaemia until the heart is reperfused in the recipient. Allograft ischaemic time is a strong risk factor for post-transplant mortality , especially when it exceeds 3–4 hours, so every e ﬀ ort must be made to keep this time period as short as possible. At retrieval cardioplegic solutions that inhibit the + + Na /K ATPase cell membrane pump or lead to cellular depolarisation and diastolic cardiac arrest are infused into the aortic root to rapidly arrest and uniformly cool the heart. Continuous heart perfusion is an alternative but more expensive and complex method of preservation. This is typ - iﬁed by the widely used Transmedics Organ Care System ( Figure 92.3 ). Ra ther than being stored in an arrested and hypothermic state, the heart is kept warm and beating. It can be managed with inotropes and monitored thr ough lactate assays, permitting longer transport times. Trials have shown that 30-day post-transplant survival is similar to standard preservation. There is some evidence to suggest that machine perfusion reduces mortality in higher risk donors and recipients and opens the potential for organ modiﬁcation and improve - ment. Other systems that utilise cold oxygenated continuous perfusion of a still heart are under investigation. To expand the current donor pool hearts may be retrieved from patients su ﬀ ering circula tory arrest (donation after cir - culatory death [DCD]) after the withdrawal of life-sustaining care and proclamation of death ( Figure 92.3 ). The heart is then rapidly retrieved and reperfused in an organ care system bef ore transport and transplantation. Clinical results appear equivalent to conventional donation and this has been a major advance. - preservation

More than 80% of potential lung grafts are declined because - of concerns over donor history , chest trauma, pneumonia or aspiration. Ideally lung donors should demonstrate standard criteria but in reality only 20% of donors actually meet these values. Those outside of the standard criteria are called extended criteria donors. Experience has shown that these organs can be safely transplanted without detrimental e ﬀ ects on survival or longer term outcome. When oxygenation of donor lungs falls below the standard criterion of 300 /uni00A0 mmHg - aggressive donor management with alveolar recruitment, ventilatory optimisation, bronchoscopy and diuretics can lead to improvements. Additionally the opiate abuse epidemic in the USA has led - to a signiﬁcant rise in the number of organ donors but with a concomitant increase in hepatitis C infection. Antiviral ther - apies, however, may enab le widespread use of such donors in - hepatitis C-negative recipients. - Summary box 92.5 - Standard criteria lung donors /uni25CF /uni25CF - /uni25CF - /uni25CF /uni25CF /uni25CF - /uni25CF /uni25CF - /uni25CF /uni25CF - Outcomes are adversely a ﬀ ected by a donor smoking his - tory of an increasing number of pack-years. Recipients of donor lungs from smokers have a higher 3-year mortality and pt - prolonged hospital stay after adjusting for age and oxygenation but this is not a consistent ﬁnding and there remains an overall surviv al beneﬁt to using lungs from heavy smoking donors to reduce waiting-list mortality . Lungs from older donors (>55 years) can be safely used to 70 years old and short-term outcomes of older donors are - similar in well-selected cases. A history of cancer in the donor does not automatically preclude lung donation. Those with a history of skin cancer , as well as certain low-grade central ner - vous system tumours, can be used with minimal risk.

Investigations Clear chest radiograph Negative Gram stain of bronchial secretions or purulent secretions Arterial oxygen tension >300 /uni00A0 mmHg (inspired oxygen fraction of 100% and positive end-expiratory pressure 5 /uni00A0 cmH O) 2 History Age <55 years Smoking <20 pack-years No chest trauma No aspiration No pneumonia

92 Heart and lung transplantation

FURTHER READING

Future perspectives

HEART TRANSPLANTATION

Heart retrieval

Heart–lung transplantation

Introduction

Introduction

LUNG TRANSPLANTATION

Learning objectives

Lung retrieval

Operative technique

Outcomes and complications

Recipient selection

SUMMARY

Ventricular assist devices

preservation