REVIEW ARTICLE
Heart-Lung Transplantation --Harefield Experience-Magdi H. YACOUB,*Asghar KHAGHANI,*Haruo MIYAMURA**andJun SONO*** ABSTRACT: One hundred and fifty-nine combined heart and lung transplantations were performed on 152 patients at Harefield Hospital from 1980 to February 1988. The age of the recipients ranged from 10 weeks to 52 years. The transplantation was indicated for pulmonary vascular disease on 106 patients (69.7 per cent), and for parenchymal lung disease on 46 patients (30.3 per cent). Eisenmenger syndrome was the commonest disease that required the heart-lung transplantation. A combination of cyclosporin A and azathiopfine was administered for immunosuppression therapy postoperatively, and oral steroids were not routinely used. The hospital mortality rate was 32.2 per cent, and 103 patients were discharged from the hospital. The first-year actuarial survival rate was 64 per cent, and the second-year was 61 per cent. Although pulmonary deterioration due to obliterative bronchiolitis was a serious late complication, most of the recipients enjoyed a good quality of life after transplantation. Heart and lung transplantation offers the patient a chance of marked improvement both in survival and in quality of life. KEY WORDS: heart-lung transplantation, cardiac transplantation, obliterative bronchiolitis, live donors
INq~RODUCTION
B e t w e e n 1980 and February, 1988, total number of 159 combined heart and lung
transplantations were performed on 152 patients at Harefield Hospital, Middlesex, England. We review in this paper the results and effectiveness of this surgery, PATIENTSAND METHODS
*Thoracic and Cardiovascular Surgical Unit, Harefield Hospital, Har~eld, Uxbridge, Middlesex, United Kingdom **The Second Department of Surgery, Niigata University, School of Medicine, Niigata, Japan ***The Department of Thoracic Surgery, Kobe City GeneralHospital, Kobe,Japan Reprint requests to: Haruo Miyamura, MD, The Second Department of Surgery, Niigata University School of Medicine, Asahi-machi 1, Niigata City 951, Japan This report is the gist of a paper read by M.H.Y. at the 88th Annual Meeting of theJapan Surgical Society, Niigata,Japan, 1988
Indications Out of 152 patients, the heart and lung transplantation was indicated for pulmonary vascular disease in 106 patients (69.7 per cent), and for parench~anal lung disease in 46 patients (30.3 per cent) (Table 1). Eisenmenger syndrome was the commonest underlying pulmonary vascular disease, followed by primary pulmonary hypertension. For the parenchymal lung disease, cystic fibrosis, emphysema, and pulmonary fibrosis were the three major underlying diseases.
J~ANESEJoi:m~ALO~~SURGERY,VOL.20, NO. 3 pp. 247-251, 1990
248
Yacoub et al.
Table 1. Indications of Heart-LungTransplantation Pulmonary Vascular Disease Primary pulmonary hypertension Eisenmenger syndrome Thrombo-embolic disease Veno-occlusive disease Secondary to LV dysfunction Complex pulmonary atresia Parenchymal Lung Disease Emphysema Pulmonary fibrosis Cystic fibrosis Destructive disease Obstructive bronchiolitis Haemoangio-lymphangioma Lymphangiomatosis Tumour
106 31 55 7 1 4 8 46 10 9 21 2 1 1 1
1
No. of Operations 159 / No. of Patients 152 ] O n e patient was suffering from alveolar cell carcinoma affecting both lungs. Procurement and transportation of donor organs Before harvesting the d o n o r heart and lungs, the d o n o r was cooled to a temperature o f 8~ using a portable heart-lung machine at the d o n o r hospital. In this way, the lungs are cooled through bronchial circulation, and a good uniform core cooling can be achieved. T h e heart and lungs were then removed en bloc and preserved in blood at 8~ These organs can be kept in this condition up to 5 hours, but usually the time used for transportation is about 3:5 hours. T h e longest distance we can cover for the d o n o r supply is 1500 miles, and in fact, d o n o r o r g a n s c o m e f r o m m a n y c o u n t r i e s in Europe, including Spain, Austria, Germany, Holland, Belgium, as well as inside of United Kingdom. Operative procedure T h r o u g h midline sternotomy, the heart is exposed, and the aorta and both vena cavae are canulated. Under extracorporeal circulation, either the right atrium or the superior and inferior vena cavae are divided. Aorta is transected just below the aortic clamp, and
1990
the heart and lungs are removed separately. T h e d o n o r heart-lungs are inserted by putting the lungs b e h i n d the phrenic nerves. The trachea is anastomosed first using monofilament absorbable sutures. T h e n the aorta is anastomosed, followed by the inferior and superior vena cavae anastomoses. Immunosuppression For the maintenance immunosuppression therapy, a combination of cyclosporin A and azathioprine is used. Because azathioprine has an effect against B-cells as well as T-cells, while cyclosporin A has its effects mainly on T-cells, this combination has several advantages. T h e dose o f cyclosporin A is 6-22 m g / k g / d a y to keep the serum level around 250-300 ng/ml, and azathioprine 0.5-1.5 mg/kg/day. We believe that it is necessary to maintain a higher level of cyclosporin A following heart-lung transplantation to prevent obliteratlve bronchiolitis. Oral steroids are not used routinely, and this has many advantages including a lower i n c i d e n c e o f systemic infections. For the treatment of acute rejection, either ATG (anti-thymocyte-globulin) or methylprednisolone, or a combination of these two is given. RESULTS Age distribution T h e age distribution and the underlying disease o f the recipients are shown in Fig. 1. T h e youngest recipient was 10 weeks of age, and the oldest 52 years. Most o f the recipients belong to young generations, and only 12.5 per cent (19/152) o f the all recipients are above 40 years of age. Hospital mortality T h e over-all hospital mortality rate was 32.2 per cent (49/152). O n e hundred and three patients survived the surgery, and were discharged from the hospital. T h e relation of the age distribution and the hospital mortality is shown in Fig. 2. T h e mortality for the patients above 40 years of age is 47.4 per cent
Volume 20 Number 3
Heart-lung transplantation
30
Table 2. Causes of Late Death after Transplantation
Age 10 weeks - 52 years N=152
27 24
7 - - ] Pulmonary Vascular Disease 106 ~ a. 18. ~8
Parenchymatous Lung Disease
46
I
Pulmonary dysfunction Chronic renal failure Suicide? Sudden death, cause? Obliterative bronchiolltis Total
z
No
Time
1 1 1 1 5
3 mths 3 mths 5 mths 11 mths 11-39 mths
9 (5.9%)
12
LzE 10
2O
30
40
50
60
Age in Years
Fig. 1. Underlying disease of heart-lung transplantation recipients.
30 84 27 84 24 ,~ 21 18 ~8 -~ 15 z
249
12
10
20
30
40
50
60
Age in Years
Fig. 2. Hospital mortality of heart-lung transplantation surgery. (9/19), which is much higher than the mortality of patients u n d e r 40 (30.1 per cent, 40/133). Although in many institutions the previous thoracotomy is regarded as a con-
traindication o f the transplantation surgery because of the excessive bleeding, we do not consider it as a contraindication. However it is quite clear that previous lateral thoracotomy is difinitely an incremental risk factor. T h e early mortality for the patients with no p r e v i o u s t h o r a c o t o m y was 3 p e r cent, whereas for the patients with one or two previous thoracotomies, it was 25 per cent, and for the patients with three or more thoracotomies, it increased up to 40 per cent. In contrast, however, the previous m e d i a n sternotomy did not affect the outcome. Late mortality ..... .: During the follow-up o f the postoperative patients, late deaths occurred in 9 patients (5.0 per cent). T h e causes o f late death are listed in Table 2. More than half of the late deaths were caused by late pulmonary deterioration due to obliterative bronchiolitis (Fig. 3). T h e over-all survival rate since the beginning of this heart-lung transplantation programme is 64 per cent at the first year, and it is 61 per cent at the second year (Fig. 4). But the clinical results are improving, and the first-year survival rate in the year 1987 among 70 recipients is 85 per cent. Postoperative pulmonary function T h e clinical investigation o f the pulmonary function after the heart-lung transplantation has b e e n done. T h e results showed that maximal oxygen consumption during dynamic exercise in heart-lung transplantation recipients is the same as in cardiac transplantation recipients, and is less than in age-matched normal control group. But the increase o f oxygen c o n s u m p t i o n can be
JPn~lJa.ySurg. 1990
Yacoub et al.
250
Table 3. Respiratory Function during Sleep SaO 2 (%)
Mean Levels Overnight PtcCO~ (mmHg)
Heart Rate
U.K S.R. L.D. B.D. N.L. LW.
96 97 94 94 97 93
53 39 50 39 40 41
81 105 84 100 88 91
Mean+SD
95.2__1.7
43.7___6.2
91.5-4-9.3
Patient
recipient completed "Boston marathon" in 1985. In spite o f the denervated heart and lungs, the breathing pattern during sleep is entirely normal, and the pulmonary function evaluated by gas exchange during the sleep is within normal limits as is shown in Table 3. T h e heart rate is usually slightly more than the normal range, because o f the denervation and the lack of vagal tone. DISCUSSION
Fig. 3. Histology of obliterative bronchiolifts. Arrows show the bronchiole, which is completely obliterated by fibrous tissue. (HE X200) % Survival 100L
Total 152
80] ~
~
6
6
%
64%
60
~
-
61%
40 20 103
87
59
42
30
1
6
12 Time in Months
18
24
Fig. 4. Actuarial survival rate of heartlung transplantation recipients. Number of patients is listed in the graph. a c h i e v e d by r e h a b i l i t a t i o n a n d exercise therapy. Indeed, one cardiac transplantation
Obliterative bronchiolitis T h e clinical results showed that the heartlung transplantation can improve the quality of life markedly) T h e biggest problem during the follow-up period is the pulmonary deterioration secondary to obliterative bronchiolitis. Once the recipient falls into this condition, the mortality rate is as high as 25 per cent. As the obliterative bronchiolitis can respond well to e n h a n c e d immunosuppression therapy, it must be an immunological p h e n o m e n o n , which can be triggered by infection. Therefore it is very important to detect this early onset. As it is known that a decline in FEV1 is an early manifestation of this complication, monthly lung function tests are mandatory for the postoperative care.
Live donors Because of the increasing d e m a n d t0r heart and combined heart-lung transplantation surgeries, we are still short o f donor organs. Recently in order to increase the d o n o r supply, we have started to use the
Volume 20 Number 3
251
Heart-lung transplantation
heart from the heart-lung transplantation recipient whenever possible. That is, the heart o f the heart-lung recipient is donated to another heart transplantation recipient. The theoretical advantages of this live donation are; 1) T h e d o n o r pool can be increased. 2) More complete assessment o f the cardiac function is possible before transplantation. 3) T h e donated heart is not subjected to haemodynamic or respiratory insults secondary to resuscitative procedures. 4) T h e d o n o r does not suffer frrom systemic infection or the neuroendocrine change during the brain death. 5) Usually the well-developed right ventricle is suitable for raised pulmonary vascular disease in the cardiac transplantation recipient. 6) Prospective HLA matching is possible. From April 1987 to March 1988, 70 patients underwent heart-lung transplantation, and 37 of them (53 per cent) were suitable for live donation o f the heart. The age distribution of the live donors (heart-lung recipients) are 15-51 (mean 29.1) years, and the heart recipients are 9-63 (mean 45.2) years. The actuarial survival rate at one year is 86 per cent for heart-lung recipients (live donors) and 78 per cent for heart recipients. After transplantation, the dilated right ventricle o f the donated heart diminishes in size, and the left ventricular ejection fraction remains
normal. T h e r e f o r e the heart transplantation from live donors (heart-lung recipients) is feasible, and the early result is satisfactory. CONCLUSION
At Harefield Hospital from 1980 to February 1988, o n e h u n d r e d a n d fifty-nine heart-lung transplantations were done. T h e age o f the recipients ranged from 10 weeks to 52 years. T h e hospital mortality was 32.2 per cent, and it was higher in the age group o f over 40 years. T h e over-all first-year survival was 64 per cent, and the second-year 61 per cent. The clinical results are improving and in 1987, the first-year survival went up to 85 per cent. T h e most serious problem during the follow-up period is the obliterative bronchiolitis, which has to be overcome by early detection and e n h a n c e d immunosuppression therapy. We conclude that the heartlung transplantation has offered patients a chance of marked improvement not only in the survival, but also in the quality of life. (Received for publication on Nov. 1, 1989) REFERENCE
1. O'Brien BJ, Banner NR, Gibson S, Yacoub M. The Nottingham Health Profile as a measure of quality of life followingcombined heart and lung transplantations.J EpidemiolCommunityHealth 1988; 42: 232-234.
Heart-Lung Transplantation --Harefield Experience-Magdi H. YACOUB,*Asghar KHAGHANI,*Haruo MIYAMURA**andJun SONO*** ABSTRACT: One hundred and fifty-nine combined heart and lung transplantations were performed on 152 patients at Harefield Hospital from 1980 to February 1988. The age of the recipients ranged from 10 weeks to 52 years. The transplantation was indicated for pulmonary vascular disease on 106 patients (69.7 per cent), and for parenchymal lung disease on 46 patients (30.3 per cent). Eisenmenger syndrome was the commonest disease that required the heart-lung transplantation. A combination of cyclosporin A and azathiopfine was administered for immunosuppression therapy postoperatively, and oral steroids were not routinely used. The hospital mortality rate was 32.2 per cent, and 103 patients were discharged from the hospital. The first-year actuarial survival rate was 64 per cent, and the second-year was 61 per cent. Although pulmonary deterioration due to obliterative bronchiolitis was a serious late complication, most of the recipients enjoyed a good quality of life after transplantation. Heart and lung transplantation offers the patient a chance of marked improvement both in survival and in quality of life. KEY WORDS: heart-lung transplantation, cardiac transplantation, obliterative bronchiolitis, live donors
INq~RODUCTION
B e t w e e n 1980 and February, 1988, total number of 159 combined heart and lung
transplantations were performed on 152 patients at Harefield Hospital, Middlesex, England. We review in this paper the results and effectiveness of this surgery, PATIENTSAND METHODS
*Thoracic and Cardiovascular Surgical Unit, Harefield Hospital, Har~eld, Uxbridge, Middlesex, United Kingdom **The Second Department of Surgery, Niigata University, School of Medicine, Niigata, Japan ***The Department of Thoracic Surgery, Kobe City GeneralHospital, Kobe,Japan Reprint requests to: Haruo Miyamura, MD, The Second Department of Surgery, Niigata University School of Medicine, Asahi-machi 1, Niigata City 951, Japan This report is the gist of a paper read by M.H.Y. at the 88th Annual Meeting of theJapan Surgical Society, Niigata,Japan, 1988
Indications Out of 152 patients, the heart and lung transplantation was indicated for pulmonary vascular disease in 106 patients (69.7 per cent), and for parench~anal lung disease in 46 patients (30.3 per cent) (Table 1). Eisenmenger syndrome was the commonest underlying pulmonary vascular disease, followed by primary pulmonary hypertension. For the parenchymal lung disease, cystic fibrosis, emphysema, and pulmonary fibrosis were the three major underlying diseases.
J~ANESEJoi:m~ALO~~SURGERY,VOL.20, NO. 3 pp. 247-251, 1990
248
Yacoub et al.
Table 1. Indications of Heart-LungTransplantation Pulmonary Vascular Disease Primary pulmonary hypertension Eisenmenger syndrome Thrombo-embolic disease Veno-occlusive disease Secondary to LV dysfunction Complex pulmonary atresia Parenchymal Lung Disease Emphysema Pulmonary fibrosis Cystic fibrosis Destructive disease Obstructive bronchiolitis Haemoangio-lymphangioma Lymphangiomatosis Tumour
106 31 55 7 1 4 8 46 10 9 21 2 1 1 1
1
No. of Operations 159 / No. of Patients 152 ] O n e patient was suffering from alveolar cell carcinoma affecting both lungs. Procurement and transportation of donor organs Before harvesting the d o n o r heart and lungs, the d o n o r was cooled to a temperature o f 8~ using a portable heart-lung machine at the d o n o r hospital. In this way, the lungs are cooled through bronchial circulation, and a good uniform core cooling can be achieved. T h e heart and lungs were then removed en bloc and preserved in blood at 8~ These organs can be kept in this condition up to 5 hours, but usually the time used for transportation is about 3:5 hours. T h e longest distance we can cover for the d o n o r supply is 1500 miles, and in fact, d o n o r o r g a n s c o m e f r o m m a n y c o u n t r i e s in Europe, including Spain, Austria, Germany, Holland, Belgium, as well as inside of United Kingdom. Operative procedure T h r o u g h midline sternotomy, the heart is exposed, and the aorta and both vena cavae are canulated. Under extracorporeal circulation, either the right atrium or the superior and inferior vena cavae are divided. Aorta is transected just below the aortic clamp, and
1990
the heart and lungs are removed separately. T h e d o n o r heart-lungs are inserted by putting the lungs b e h i n d the phrenic nerves. The trachea is anastomosed first using monofilament absorbable sutures. T h e n the aorta is anastomosed, followed by the inferior and superior vena cavae anastomoses. Immunosuppression For the maintenance immunosuppression therapy, a combination of cyclosporin A and azathioprine is used. Because azathioprine has an effect against B-cells as well as T-cells, while cyclosporin A has its effects mainly on T-cells, this combination has several advantages. T h e dose o f cyclosporin A is 6-22 m g / k g / d a y to keep the serum level around 250-300 ng/ml, and azathioprine 0.5-1.5 mg/kg/day. We believe that it is necessary to maintain a higher level of cyclosporin A following heart-lung transplantation to prevent obliteratlve bronchiolitis. Oral steroids are not used routinely, and this has many advantages including a lower i n c i d e n c e o f systemic infections. For the treatment of acute rejection, either ATG (anti-thymocyte-globulin) or methylprednisolone, or a combination of these two is given. RESULTS Age distribution T h e age distribution and the underlying disease o f the recipients are shown in Fig. 1. T h e youngest recipient was 10 weeks of age, and the oldest 52 years. Most o f the recipients belong to young generations, and only 12.5 per cent (19/152) o f the all recipients are above 40 years of age. Hospital mortality T h e over-all hospital mortality rate was 32.2 per cent (49/152). O n e hundred and three patients survived the surgery, and were discharged from the hospital. T h e relation of the age distribution and the hospital mortality is shown in Fig. 2. T h e mortality for the patients above 40 years of age is 47.4 per cent
Volume 20 Number 3
Heart-lung transplantation
30
Table 2. Causes of Late Death after Transplantation
Age 10 weeks - 52 years N=152
27 24
7 - - ] Pulmonary Vascular Disease 106 ~ a. 18. ~8
Parenchymatous Lung Disease
46
I
Pulmonary dysfunction Chronic renal failure Suicide? Sudden death, cause? Obliterative bronchiolltis Total
z
No
Time
1 1 1 1 5
3 mths 3 mths 5 mths 11 mths 11-39 mths
9 (5.9%)
12
LzE 10
2O
30
40
50
60
Age in Years
Fig. 1. Underlying disease of heart-lung transplantation recipients.
30 84 27 84 24 ,~ 21 18 ~8 -~ 15 z
249
12
10
20
30
40
50
60
Age in Years
Fig. 2. Hospital mortality of heart-lung transplantation surgery. (9/19), which is much higher than the mortality of patients u n d e r 40 (30.1 per cent, 40/133). Although in many institutions the previous thoracotomy is regarded as a con-
traindication o f the transplantation surgery because of the excessive bleeding, we do not consider it as a contraindication. However it is quite clear that previous lateral thoracotomy is difinitely an incremental risk factor. T h e early mortality for the patients with no p r e v i o u s t h o r a c o t o m y was 3 p e r cent, whereas for the patients with one or two previous thoracotomies, it was 25 per cent, and for the patients with three or more thoracotomies, it increased up to 40 per cent. In contrast, however, the previous m e d i a n sternotomy did not affect the outcome. Late mortality ..... .: During the follow-up o f the postoperative patients, late deaths occurred in 9 patients (5.0 per cent). T h e causes o f late death are listed in Table 2. More than half of the late deaths were caused by late pulmonary deterioration due to obliterative bronchiolitis (Fig. 3). T h e over-all survival rate since the beginning of this heart-lung transplantation programme is 64 per cent at the first year, and it is 61 per cent at the second year (Fig. 4). But the clinical results are improving, and the first-year survival rate in the year 1987 among 70 recipients is 85 per cent. Postoperative pulmonary function T h e clinical investigation o f the pulmonary function after the heart-lung transplantation has b e e n done. T h e results showed that maximal oxygen consumption during dynamic exercise in heart-lung transplantation recipients is the same as in cardiac transplantation recipients, and is less than in age-matched normal control group. But the increase o f oxygen c o n s u m p t i o n can be
JPn~lJa.ySurg. 1990
Yacoub et al.
250
Table 3. Respiratory Function during Sleep SaO 2 (%)
Mean Levels Overnight PtcCO~ (mmHg)
Heart Rate
U.K S.R. L.D. B.D. N.L. LW.
96 97 94 94 97 93
53 39 50 39 40 41
81 105 84 100 88 91
Mean+SD
95.2__1.7
43.7___6.2
91.5-4-9.3
Patient
recipient completed "Boston marathon" in 1985. In spite o f the denervated heart and lungs, the breathing pattern during sleep is entirely normal, and the pulmonary function evaluated by gas exchange during the sleep is within normal limits as is shown in Table 3. T h e heart rate is usually slightly more than the normal range, because o f the denervation and the lack of vagal tone. DISCUSSION
Fig. 3. Histology of obliterative bronchiolifts. Arrows show the bronchiole, which is completely obliterated by fibrous tissue. (HE X200) % Survival 100L
Total 152
80] ~
~
6
6
%
64%
60
~
-
61%
40 20 103
87
59
42
30
1
6
12 Time in Months
18
24
Fig. 4. Actuarial survival rate of heartlung transplantation recipients. Number of patients is listed in the graph. a c h i e v e d by r e h a b i l i t a t i o n a n d exercise therapy. Indeed, one cardiac transplantation
Obliterative bronchiolitis T h e clinical results showed that the heartlung transplantation can improve the quality of life markedly) T h e biggest problem during the follow-up period is the pulmonary deterioration secondary to obliterative bronchiolitis. Once the recipient falls into this condition, the mortality rate is as high as 25 per cent. As the obliterative bronchiolitis can respond well to e n h a n c e d immunosuppression therapy, it must be an immunological p h e n o m e n o n , which can be triggered by infection. Therefore it is very important to detect this early onset. As it is known that a decline in FEV1 is an early manifestation of this complication, monthly lung function tests are mandatory for the postoperative care.
Live donors Because of the increasing d e m a n d t0r heart and combined heart-lung transplantation surgeries, we are still short o f donor organs. Recently in order to increase the d o n o r supply, we have started to use the
Volume 20 Number 3
251
Heart-lung transplantation
heart from the heart-lung transplantation recipient whenever possible. That is, the heart o f the heart-lung recipient is donated to another heart transplantation recipient. The theoretical advantages of this live donation are; 1) T h e d o n o r pool can be increased. 2) More complete assessment o f the cardiac function is possible before transplantation. 3) T h e donated heart is not subjected to haemodynamic or respiratory insults secondary to resuscitative procedures. 4) T h e d o n o r does not suffer frrom systemic infection or the neuroendocrine change during the brain death. 5) Usually the well-developed right ventricle is suitable for raised pulmonary vascular disease in the cardiac transplantation recipient. 6) Prospective HLA matching is possible. From April 1987 to March 1988, 70 patients underwent heart-lung transplantation, and 37 of them (53 per cent) were suitable for live donation o f the heart. The age distribution of the live donors (heart-lung recipients) are 15-51 (mean 29.1) years, and the heart recipients are 9-63 (mean 45.2) years. The actuarial survival rate at one year is 86 per cent for heart-lung recipients (live donors) and 78 per cent for heart recipients. After transplantation, the dilated right ventricle o f the donated heart diminishes in size, and the left ventricular ejection fraction remains
normal. T h e r e f o r e the heart transplantation from live donors (heart-lung recipients) is feasible, and the early result is satisfactory. CONCLUSION
At Harefield Hospital from 1980 to February 1988, o n e h u n d r e d a n d fifty-nine heart-lung transplantations were done. T h e age o f the recipients ranged from 10 weeks to 52 years. T h e hospital mortality was 32.2 per cent, and it was higher in the age group o f over 40 years. T h e over-all first-year survival was 64 per cent, and the second-year 61 per cent. The clinical results are improving and in 1987, the first-year survival went up to 85 per cent. T h e most serious problem during the follow-up period is the obliterative bronchiolitis, which has to be overcome by early detection and e n h a n c e d immunosuppression therapy. We conclude that the heartlung transplantation has offered patients a chance of marked improvement not only in the survival, but also in the quality of life. (Received for publication on Nov. 1, 1989) REFERENCE
1. O'Brien BJ, Banner NR, Gibson S, Yacoub M. The Nottingham Health Profile as a measure of quality of life followingcombined heart and lung transplantations.J EpidemiolCommunityHealth 1988; 42: 232-234.
