Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992

Cystic fibrosis: lung transplantation. A

F Welis MS FRCS

N Caine BA

new

L Sharples PhD

option-a

new

J Wallwork MB FRCS

dilemma!

Transplant Unit,

Papworth Hospital, Papworth Everard, Cambridge CB3 8RE Keywords: cystic fibrosis; heart-lung transplantation

Introduction Cystic fibrosis (CF) is the commonest lethal multiorgan genetic disorder in Caucasians (1:2000 live births)'. Most patients die of pulmonary insufficiency as a result of recurrent infections and progressive lung destruction. The need exists for a satisfactory treatment for this problem. Heart and lung transplantation (HLT) became a clinical reality in March 1981 at Stanford University, California, when Reitz and colleagues began clinical trials. This was the culmination of an extensive laboratory research programme and was encouraged by the availability of the new immunosuppressant agent cyclosporin-A2. HLT was initially offered to patients with pulmonary vascular disease resulting from primary pulmonary hypertension or from congenital heart defects, and then to patients with non-suppurative lung diseases. No patients with suppurative lung disease were considered suitable because of concerns of overwhelming sepsis in the transplanted lungs exacerbated by immunosuppression. The presence of chronic

pulmonary infection in CF patients together with multi-organ involvement, poor nutritional status and the fear that the disease may recur in the transplanted organs were all concerns when HLT was considered in CF patients. With experience however, the results of HLT improved and the possibility of this treatment for end-stage pulmonary disease in CF patients was again considered. The transplantation of one lung was not regarded as an option because of the risk of cross-infecting the transplanted lung and overwhelming uncontrollable infection in the non-transplanted lung as a result of immunosuppression. At that time no

other surgical options were clinically available. The first HLT for CF at Papworth Hospital was carried out in 19853. From 1987, when a transplant programme for children was initiated at Great Ormond Street, a joint venture was embarked upon between the two institutions. Between November 1982 and June 1991 there were a total of 796 patients referred to the unit to be considered for HLT (378 male and 418 female). Three hundred and twenty-five patients were admitted for our assessment programme (151 male and 174 female). There are currently 79 patients awaiting admission for assessment for HLT. Of those patients who have been assessed, 215 have been accepted for transplantation. Seventy-one were placed on a provisional list. One hundred and six had been transplanted by the end of June 1991. Sixty patients had died whilst waiting for operation and 46 patients are still awaiting HLT. Of the 215 patients accepted for HLT 77 were people with CF and 34 of these have received a HLT. Twelve

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31-35

36-40

Ages of patients transplanted (years)

Figure 1. Age distribution of CFpatients (n=34) transplanted (mean age=24.2 years)

people with CF are currently awaiting HLT. One patient received a heart-lung-liver transplant. The sex distribution of those transplanted was evenly distributed and the mean age was 24.2 years (+5.03) (Figure 1). Twenty-six patients died waiting for transplantation. Criteria for selection Patients seen for assessment were accepted for HLT if they had a life expectancy of less than 18-24 months and if their quality of life was severely impaired by respiratory disease. The following parameters were compiled to assess the severity of CF: (1) Pulmonary function testing; mainly the forced expiratory volume in one second (FEV,). A value below 30% of the predicted value indicated advanced airway obstruction and severe disease. (2) Exercise tolerance. A 12-min walking distance of less than 500 metres is a sign of serious impairment4. (3) Tachycardia at rest, systemic arterial oxygen desaturation, the inability to regain weight between respiratory exacerbations, frequent and prolonged admission to hospital and congestive heart failure are all consistent with end stage disease. (4) The Schwachman-Kulczycki scoring system5 which monitors chest radiograph, physical examination, physical activity and nutrition, was particularly useful in children. Maximum is 100 points. Severe disability is less than 40 points. When assessing CF patients for transplantation these parameters are evaluated in the context ofthe overall clinical trend. Some patients are clearly terminally ill. Others are placed on a provisional list and as their condition deteriorates they are transferred to the active list. Moribund patients however, do not do well, and patients at the advanced stage of their illness are not generally transplanted. In the pre-treatment work-up a full cardiac assessment is carried out so that in the event of a transplant

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10 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 100

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80 >

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co

.e 40-

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0-3 12 24 Months after assessment

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Figure 2. Survival from assessment for transplant (- n=34) and non-transplant (- - - n=43) patients

6-12 34 -; Months after transplant

>12

Figure 3. Histogram to show rejection rates for CF(E, n=34) and non-CF (i, n= 72) patients

CF patient with a sound heart may become in turn cardiac donor for another patient. In that way the heart is not wasted. This procedure has been referred to as a 'Domino' procedure. the

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Exclusion criteria The principle exclusion criteria are as follows: (1) Previous pleurectomy for pneumothorax. (2) Aspergilloma involving the pleura or chest wall. (3) Advanced liver disease is a relative contraindication, but heart, lung and liver transplantation has been carried out twice at our institution with good result. A history of diabetes mellitus, low dose steroid therapy, growth of Aspergillus fumigatus in the sputum, and previous thoracotomy (other than for pleurectomy or pleurodesis) are no longer contraindications for HLT. Donor selection and management, organ preservation and operative techniques will not be considered firther here as they are beyond the scope of this article. Survival without HLT The survival from the time of assessment for transplant and non-transplant patients is shown in Figure 2. This reflects a 40% reduction in the risk of death in the transplant group. The most important predictors of survival in the absence of a transplant are pCO2, weight/height ratio and a severely impaired 12 min walk (Table 1).

Results of HLT in CF patients Of the 34 patients with CF who received a heart-lung transplant 25 were alive at 1-65 months after surgery. Nine have died: four from recurrent rejection and super-added infection, and one each from aspiration pneumonia, tracheal dehiscence, candidal septicaemia, adult respiratory distress syndrome and cerebo-vascular accident. At 3 months post-transplant mean percentage predicted FEV was 88%. Episodes of rejection occurred at 3.62 (0.38) per hundred

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1.5

u4

0.5 0

0-3

OR (95% Cl)

days (Figure 3) and infection at 2.03 (0.24) per hundred days (Figure 4) during the first 3 months. The infection rate was not increased when compared with patients undergoing HLT who did not suffer from CF.

.Acttarial survival at one year of 79% and 66% at 2 years in the CF patients undergoing LILT compares favourably with 78% and 63% for the entire ILT

population (Figure 5). Quality of life of CF patients before and after ILT To measure quality of life, two questionnaires were completed by patients at intervals before and after transplantation. The first of these is the Nottingham Health Profile (NHHP) which in two parts measures aspects of physical, social and emotional health status and establishes the extent to which current healthstate is causing problems in seven areas of daily living. The second questionnaire provides details of symptoms, activity restrictions and dependence levels. Of those CF patients accepted for HILT between August 1985 and December 1990, 60 completed Quality of Life (QOL) details. Thirty patients had received a heart-lung transplant of whom 20 patients completed QOL data before and after surgery. There was no difference in the NHP data when comparing the transplant and non-transplant grotips at the time of acceptance. Comparing NHP data 100 -

-80-

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_ __,- Non cystic fibrosis (n=72)

, 60-

FEV1 (per litre) FEV, (per % pred)

Minimum sat °2 during 12 min walk (per %) PC02 (per kPa) Weight/height (%)

0.28 (0.08, 0.98) 0.96 (0.92, 1.00) 1.02 (0.99, 1.04)

0.05 0.04 0.25

1.44 (1.17, 1.77) 0.96 (0.92, 0.99)

0.0005 0.008

All other measurements non-significant

>12

Figure 4. Histogram to show infection rates for CF a, n=34) and non-CF (i, n=72) patients

Table 1. Summary of the most important prediction of survival for CF patients in the absence of a transplant

Variable

3-6 6-12 Months after transplant

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ie

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Cystic fibrosis (n=34)

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0

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3 4 Year after transplant

5

6

Figure 5. Graph to show CF (n=34) and non-CF (n=72) patient survival for the whole group of HLT patients

Journal of the Royal- Society of Medicine Supplement No.- 19 Volume 85 1992 11

before and at 3-6 months after transplantation, there potential problem howeverv and has resulted in a was improvement in all limensions of the NHP, significant number- of patients requiring an- endodifferences which r&ched statistical significance in bronchial stent in sffme series9. Although this salvage physical mobility, energy and emotional reactions technique lis appliable in adults, the reduction: in (P< 0.05). luminal diameter which occurs in thesinall airways Patients experienci npg breatWessness most or all of of children can be critical. Techniques are available the time changed from 61.19's pre-transplant to 5.6% to minimize the problem, such -as ensuring the at 3-6 months after. Home, leisure aud social activity bronchial stump is kept as short as possible with as restrictions were experienced by 90% of patients pre. little 4issection around it as is commensurate with transplant compared with 30-40% at 3-6 months --satisfactory anastomosis to reduce ischaemia akid after. All patients were undergoing physiotherapy for telescoping the donor bronchus -inside that of the between 1 and 4 hours a day pre transplant; whereas recipient. None of these practical points has elimiated at 3-6 months after surgery 70% of patients were free the -problem however. In comparison airway complicaof physiotherapy. tions have been rare in our series of HLT patients, witxh only two tracheal dehiscences occurring in 106 Alternative procedures to HLT transplants. Few other units in the world have been able to match Severe haemorrhage from multiple- dense vascular the size and results of this series largely as a result adhesions in the pleural space of patients with of a shortage in donor organs. This has been a suppurative lung disease has been used by some as particular problem in the USA where there has been an argument against HLT for CF. It has been a proliferation of cardiac transplant units utilizing suggested that the modified bilateral transverse hearts, but who do not have a lung or HLT thoraootomy (clam shell) refered to above improves programme. This has led to other workersithinking surgical exposure and that the double sequential lung again about lung transplantation without the heart, transplant without bypass minimizes the-bleeding for suppurative lung disease, including CF p-atienta. probletns. Although bleeding is undoubtedly a hazard There has been an evolution of techniques and ideas.' in HLT procedures for CF patients', we have not found Cooper and colleagues of the Toronto General it to be in any way prohibitive. Indeed, with the Hospital developed the technique of double-lung en advent of Trasylol (aprotinin) and good surgical bloc transplantation specifically with this problem in technique this has not been a major problem in our mind6. They argued that only the diseased organs series. were being removed and that the recipient need not Another argument in favour ofthe sequential single give up his/her own heart unnecessarily. Thus lung technique is that the recipients retain their own obviating the risk of cardiac rejection and early graft innervated heart. This is said to allow better coronary atherosclerosis described in the heart only adjustment to exercise. The Toronto lung group transplant recipient. In this technique there are three produced data to show that the response to autonomic stimuli in the double lung en bloc recipient was anastomoses, namely the trachea, the common pulmonary artery and a cuff of donor left atrium no better than for a cardiac transplant recipient where denervation is known to be complete'0. This containing the pulmonary veins. Others around the world have echoed these thoughts may not be so in the double sequential single and proceeded along similar lines7. Numbers remain lung transplant patients where the hilum is less disturbed and hence innervation of the heart small, however, such that direct comparison of results with larger single centre series, such as those from maintained. Papworth3 and Harefield hospitals are not possible. The main problem encountered with the double The way ahead lung-en bloc procedure has been poor healing and Clearly the management by transplantation of end breakdown of the tracheal anastomosis. This stage pulmonary suppurative disease in CF is still continued to be a problem despite wrapping the evolving. anastomosis with omentum, a structure well known Although the double-lung en bloc technique is and widely used for its ability to encourage probably already obsolete, other than for small neovascularization. This technique had first been children, the double sequential single lung procedure employed to encourage satisfactory healing of the is seen by many as the natural successor to HLT in bronchus in single lung transplants8. this condition. Little data is yet available to support It is likely that the separation of the heart from the this contention however, either in the mid or short lung severely disrupts the collateral mediastinal term. Heart and lung with a domino transplant of the circulation to the carina thus worsening the ischaemia recipients own heart has now a very good established of this region. In an attempt to address this problem, record. Survival is high (78% at one year) with few the technique of double sequential single lung airway complications. In addition, the results of the transplantation has evolved. In this procedure domino heart procedure are equally as good as those sequential pneumonectomies with the grafting of each for conventional donor organs. Theoretically they may donor lung in turn is performed. Initially carried out be even better as a result of a shorter donor heart through bilateral lateral thoracotomies, the so called ischaemic time, as the heart is simply transferred 'clam-shell' bilateral anterior transverse thoracotomy from one theatre to another next door. with sternal transection is now preferred. This can There is now, however, an ethical issue to be be completed without the use of cardio-pulmonary addressed. That is, should a patient with a normal bypass in many patients as each lung in turn takes heart be asked to give up that heart for someone else when a procedure now exists that provides two new up its function. In this situation the mediastinal collateral supply to the carina is undisturbed and lungs, satisfying the true clinical needs of the patient healing of each bronchial anastomosis is said to be with end stage lung disease?" Further experience is improved. Bronchial anastomotic stenosis is still a required to answer these critically important questions.

12 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992

The following issues remain to be resolved. Firstly, the potentially enhanced cardiac response to exercise in the double sequential lung procedure. Is this important if only measurable at peak exercise? Secondly, what will be the problems as a result of bronchial stenosis in the bilateral sequential double lung group? And finally, what will be the long term problems relating to endobronchial stents? Both HLT and double lung transplant recipients have been shown to develop bronchiolitis obliterans at similar rates. Other problems such as CMV pneumonia and rejection are comparable in both groups.

The next few years may see an answer to these fascinating questions, but in the meantime heart and lung transplantation offers a satisfactory treatment for those unfortunate CF patients with end stage pulmonary disease. References 1 Wood RE, Boot TF, Doershuk CF. State of the art: cystic fibrosis. Am Rev Respir Dis 1976;113:833-78 2 Reitz BA, Wallwork J, Hunt SA, et aL Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982;306: 557-64

3 de Leval MR, Smyth R, Whitehead B, et al. Heart and Lung transplantation for terminal cystic fibrosis. A 4% year experience. J Thorac Cardiovasc Surg 1991;101: 633-42 4 McGavin CR, Artiniti M, Nave H, McHardy GJ. Dyspnoea diability and distance walked: comparison of estimates of exercise performance in respiratory disease. BMJ 1978;2:241-4 5 Schwachman H, Kulczycki LL. Long term study of one hundred and five patients with cystic fibrosis. Am JDis Child 1958;96:6-15 6 Patterson GA, Cooper JD, Dark JH, et al. Experimental and clinical double lung transplantation. J Thorac Cardiovasc Surg 1988;95:70-4 7 Noirclerc M, Shennib H. Double lung transplantation for cystic fibrosis. JHeart Lung Transplatation 1991;10:154 8 Lima 0, Goldberg M, Peters WJ, Ayabe H, Townsend E, Cooper JD. Bronchial omentopexy in canine lung transplantation. J Thorac Cardiovasc Surg 1982;83:418-21 9 Schafers HJ, Haydock DA, Cooper JD. The prevalence and management of bronchial anastamotic complications in lung transplantation. J Thorac Cardiovasc Surg 1991;101:1044-52 10 Carere R, Patterson GA, Lin P, Williams T, Maurer J, Grossman R. Right and left ventricular performance after single and double lung transplantation. J Thorac Cardiovasc Surg 1991;102:115-23 11 Cooper JD. Dominoes-pragmatism or piracy? Transplant Int 1991;4:1-2

Cystic fibrosis: lung transplantation. A new option--a new dilemma!

Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 Cystic fibrosis: lung transplantation. A F Welis MS FRCS N Caine BA new...
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