Royal Brompton Grand Rounds Heart-lung transplantation for cystic fibrosis Can be successful despite contraindications About 6500 people in Britain have cystic fibrosis and only half of patients reach 19 years of age.' Despite recent improvements in treatment there is still a considerable morbidity and mortality.2 The main cause of death is respiratory failure from chronic respiratory infection. Heart-lung transplantation for cystic fibrosis was first successfully carried out in 1985, and over 100 patients have now received transplants in Britain.34
he had had bilateral pleurodesis and was also diabetic and taking steroids. There were no data to show that these factors are absolute contraindications so we performed the operation. The donor organs were from a man aged 31 who had died in a road traffic accident. The ischaemic time was 2 hours 35 minutes. As expected, there were many adhesions in the pleural cavities and considerable bleeding. POSTOPERATIVE CARE
Royal Brompton National Heart and Lung Hospital, London SW3 6HP Case presented by: B PMadden,MrCPi, MRCPI senior transplant registrar M E Hodson, FRCP, reader in
Braspladen,
respiratory medicine
M H Yacoub, FRCS, professor ofcardiothoracic surgery
Discussion group: E W F W Alton,MRcP,
PeJtBrnes, professor ' thoBrac medici thoracic medicine D M Denison, FRCP
lecturer in medicine FRCP
o
e
professor of clinical physiology A B Kay, FRCP, professor of allergy and clinical
immunology-
A Newmdn-Taylor, FRCP, consultant physician D M Geddes, FRCP, consultant physician Series edited by:
Dr K F Chung
BMJ 1992;304:835-6
Case history A 29 year old man-had had cystic fibrosis cliagnosed at the age of 4 years when he presented vwith malabsorption. At 14 years he had developed recurrent chest infections. Clinical treatment con,sisted of pancreatic enzymes, vitamins, chest physi otherapy, antibiotics, and bronchodilators. In 1975 he Ihad had a left abrasion pleurodesis and in 1981 a right abrasion pleurodesis for recurrent pneumothoraces. H( required * to relieve . airflow *: . obstruction and subcorticosteroids sequently developed diabetes mellitus. By January 1988 he had become too ill to work and had cleveloped heart failure. At that time his forced expiratotry volume in one second was 540 ml, his forced vital cap)acity was 2000 ml, and his blood gases breathing air were pH 7-42, partial pressure of oxygen 6-0kPa, arnd partial pressure of carbon dioxide 7 6 kPa. CultuIre of his sputum grew Pseudomonas aeruginosa. A ch.est radiograph (fig 1 (left)) showed bronchiectasis aLnd upper zone fibrosis. Computed tomography confirtned these findings and showed extensive bilateralI pleural reaction. He was assessed for an urgent hLeart-lung transplantation. His condition rapidly deiteriorated and his partial pressure of carbon dioxide reached 10 kPa. He was intubated and ventilation waiS started. A few days later suitable donor organs becaine avail-
able.
THE OPERATION
TheO erATIoN There were some problems in accepting thlis patient for transplantation. He was being ventilate-d, which many units regard as an absolute contraindic2ation, and
The patient was routinely immunosuppressed with azathioprine (2 mg/kg/day), cyclosporin A (aiming at achieving whole blood concentrations of 500ng/ml in the first postoperative month), and rabbit antithymocyte immunoglobulin (100 mg on alternate days for the first 10 postoperative days). He experienced episodes of acute pulmonary rejection (fever, fall in oxygen' saturation, abnormal appearance on chest radiography, and reduction in respiratory function) on the 13th, 18th, 24th, and 34th postoperative days. The diagnosis was confirmed at bronchoscopy, when histological examination of transbronchial lung biopsy specimens showed perivascular cuffing with mononuclear cells. He was successfully treated on each occasion by pulsed doses of intravenous methylprednisolone (1 g intravenously thrice daily). As appropriate to the antibiotic sensitivities of the pseudomonas isolated from his sputum immediately before surgery, he was started on ciprofloxacin and imipenem for the first 10 postoperative days together with -inhaled colistin sulphate. On the 10th postoperative day Candida albicans was isolated from his sputum and, in the absence of radiological change, he was successfully treated with nebulised amphotericin. He required intravenous antibiotics for pseudomonal respiratory infections three times and for Staphylococcus aureus pneumonia once in the first two postoperative months. At the beginning of the third postoperative month he developed a fever of 40°C associated with hypoxia, and diffuse interstitial shadowing was visible on a chest radiograph. Transbronchial lung biopsy confirmed the diagnosis of cytomegalovirus pneumonitis (fig 2), which was successfully treated with a combination of intravenous ganciclovir and hyperimmune globulin to cytomegalo-
Other postoperative complications encountered prolonged intubation and ventilation for 11 weeks, which necessitated the insertion of a tracheostomy tube; a left haemothorax requiring the insertion of a chest drain; systolic hypertension requiring treatment with nifedipine; diffuse peripheral oedema secondary to hypoalbuminaemia; and abnormal liver function probably secondary to azathioprine treatment -liver function returned to normal after temporary withdrawal of the drug. The man was discharged from hospital three months after surgery. However one month later he became acutely ill while away from home and on arrival at Harefield Hospital he developed a cardiorespiratory arrest. He was resuscitated and was hypotensive, FIG 1-Chest radiograph before (left) and three months after (right) transplantation. Before tra npiantation clinically septic, and in acute renal failure. He required typical features of cystic fibrosis are visible with bronchial wall thickening and overinflated lu'ngs. There is inotropic support, replacement fluid therapy, and evidence ofprevious thoracotomies for bilateral pleurodesis haemofiltration. A bronchoscopy was done and the were:
BMJ VOLUME 304
28 MARCH 1992
835
A~~~~~~~~
FIG 2-Lung biopsy specimen staned with haematoxyln and eosn showing multiple cytomegalovirus inclusion bodies (arrows)
bronchial tree was found to be full of secretions, from which Streptococcus pneumoniae was isolated. He was treated with intravenous benzylpenicillin and given azathioprine and hydrocortisone for immunosuppression. He responded well to treatment and was discharged from hospital two weeks later. Three years after the transplant operation he was back at work and took regular exercise: walking, cycling, and swimming. A radiograph showed that his chest was clear (fig 1 (right)); his forced expiratory volume was 3 1 and forced vital capacity was 3-5 1. His immunosuppressive regimen was cyclosporin 8 mg/kg! day, azathioprine 100 mg daily, and prednisolone 5 mg daily. Comments Postoperative complications of heart-lung transplantation include acute rejection, infection, renal failure, multiorgan failure, seizures, lymphoproliferative disorders, and bronchiolitis obliterans. Patients with cystic-fibrosis may also develop other problems. Firstly, they may have malabsorption of cyclosporin A and thus require higher doses. Secondly, they are prone to pseudomonal respiratory infections. Dual antipseudomonal antibiotic treatment is given intravenously for the first 10 postoperative days together with long term inhaled colistin sulphate. Thirdly, liver disease may preclude patients from taking azathioprine. Fourthly, often patients cannot quickly start eating. In such patients we use an elemental diet given nasogastrically or through a gastrostomy tube. Fifthly, they may have meconium ileus equivalent, which should be treated by Nacetylcysteine. Sixthly, hyponatraemia in these patients can be exacerbated by diuretics. Lastly, patients may have diabetes mellitus and require an insulin infusion over the operative and immediate postoperative period. Heart-lung transplantation started in the early 1980s and was initially confined to patients with pulmonary vascular conditions. We were particularly worried about treating patients who had pulmonary infection and there was also concern that cystic fibrosis might recur in the transplanted lung. We have performed 275 heart-lung transplant operations in our unit, of which 79 were for cystic fibrosis. Heart-lung transplantation is the most common operation, although bilateral single lung transplantation is another option. One of the critical considerations in deciding on the operation is the blood supply to the bifurcation of the trachea. During the operation we only anastomose the pul-
836
monary artery, the pulmonary veins, and the airways and anastomosis of the bronchial arteries until recently has not been attempted. In transplanting the heartlung block there is a good blood supply from the coronary arteries to the area ofthe tracheal anastomosis, which usually heals well. Transplantation of both lungs without the heart is often associated with airway anastomotic problems. Our patient had several high risk factors-namely ventilation, bilateral pleurodesis, diabetes, and steroid treatment. We have now shown that the overall survival of patients with supposed high risk factors can be very encouraging.5 The overall survival to one year of our first 52 patients with cystic fibrosis was 69%. In most patients the lung function has been well maintained for over three years. Nevertheless, obliterative bronchiolitis is a risk for patients after heart-lung or single lung transplantation.
Discussion EWFWA: What is the relation between preoperative and postoperative pseudomonal types? MEH: No clear relation has so far been shown, but we are currently studying this using DNA typing. There does, however, seem to be a relation between the type of pseudomonas in the patient's upper airways and the pseudomonas found in the transplanted lung. PJB: What do you think of the new immunosuppressive compound FK506? MHY: It is a promising drug and most of the early work has been done on patients receiving liver transplants. We await developments. DMD: How long does the transplanted lung retain its genetic identity? MHY: Some studies on the heart and some on the lung show that the HLA identity of the cardiac monocytes and endothelium remains that of the donor, five years after transplantation. ABK: Have you considered using cyclosporin sparing strategies or inhaled cyclosporin? MHY: Routinely we use azathioprine together with cyclosporin. We avoid corticosteroids whenever possible and reserve them for treating episodes of rejection. We also use monoclonal antibodies to T lymphocytes, but these do not seem as promising as previously thought. We have no experience with inhaled cyclosporin. ANT: What are the causes of obliterative bronchiolitis? MHY: There is evidence that it is a manifestation of rejection and that it is the counterpart of the accelerated coronary artery sclerosis seen in recipients of heart transplants or the arterial disease seen in recipients of kidney and liver transplants. DMG: What are the chances of removing both lungs at once and then transplanting a single lung, and what about using animal organs? MHY: I would be very worried about leaving a pneumonectomy space in an immunosuppressed patient, which would be a source of infection and empyema. As far as animal organs are concerned more work needs to be done. I British Paediatric Association Working Party on Cystic Fibrosis. Cystic fibrosis in the United Kingdom 1977-85: an improving picture. BMJ 1988;297:
1599-602. 2 Penketh ARL, Wise A, Mearns MP, Hodson ME, Batten JC. Cystic fibrosis in adolescents and adults. Thorax 1987;42:526-32. 3 Scott J, Hunter J, Stewart S, Higenbottam T, Hodson M, Penketh A, et al. Heart-lung transplantation for cystic fibrosis. Lancet 1988;ii: 192-4. 4 Yacoub MH, Banner NR, Khaghani A, Fitzgerald M, Madden B, Tsang V, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Transplant 1990;9:459-67. 5 Tsang V, Madden BP, Hodson ME, Yacoub ME. Heart-lung transplantation for cystic fibrosis. Pediatr Pulmonol 1990;supplS:256.
BMJ
VOLUME
304
28
MARCH
1992
he had had bilateral pleurodesis and was also diabetic and taking steroids. There were no data to show that these factors are absolute contraindications so we performed the operation. The donor organs were from a man aged 31 who had died in a road traffic accident. The ischaemic time was 2 hours 35 minutes. As expected, there were many adhesions in the pleural cavities and considerable bleeding. POSTOPERATIVE CARE
Royal Brompton National Heart and Lung Hospital, London SW3 6HP Case presented by: B PMadden,MrCPi, MRCPI senior transplant registrar M E Hodson, FRCP, reader in
Braspladen,
respiratory medicine
M H Yacoub, FRCS, professor ofcardiothoracic surgery
Discussion group: E W F W Alton,MRcP,
PeJtBrnes, professor ' thoBrac medici thoracic medicine D M Denison, FRCP
lecturer in medicine FRCP
o
e
professor of clinical physiology A B Kay, FRCP, professor of allergy and clinical
immunology-
A Newmdn-Taylor, FRCP, consultant physician D M Geddes, FRCP, consultant physician Series edited by:
Dr K F Chung
BMJ 1992;304:835-6
Case history A 29 year old man-had had cystic fibrosis cliagnosed at the age of 4 years when he presented vwith malabsorption. At 14 years he had developed recurrent chest infections. Clinical treatment con,sisted of pancreatic enzymes, vitamins, chest physi otherapy, antibiotics, and bronchodilators. In 1975 he Ihad had a left abrasion pleurodesis and in 1981 a right abrasion pleurodesis for recurrent pneumothoraces. H( required * to relieve . airflow *: . obstruction and subcorticosteroids sequently developed diabetes mellitus. By January 1988 he had become too ill to work and had cleveloped heart failure. At that time his forced expiratotry volume in one second was 540 ml, his forced vital cap)acity was 2000 ml, and his blood gases breathing air were pH 7-42, partial pressure of oxygen 6-0kPa, arnd partial pressure of carbon dioxide 7 6 kPa. CultuIre of his sputum grew Pseudomonas aeruginosa. A ch.est radiograph (fig 1 (left)) showed bronchiectasis aLnd upper zone fibrosis. Computed tomography confirtned these findings and showed extensive bilateralI pleural reaction. He was assessed for an urgent hLeart-lung transplantation. His condition rapidly deiteriorated and his partial pressure of carbon dioxide reached 10 kPa. He was intubated and ventilation waiS started. A few days later suitable donor organs becaine avail-
able.
THE OPERATION
TheO erATIoN There were some problems in accepting thlis patient for transplantation. He was being ventilate-d, which many units regard as an absolute contraindic2ation, and
The patient was routinely immunosuppressed with azathioprine (2 mg/kg/day), cyclosporin A (aiming at achieving whole blood concentrations of 500ng/ml in the first postoperative month), and rabbit antithymocyte immunoglobulin (100 mg on alternate days for the first 10 postoperative days). He experienced episodes of acute pulmonary rejection (fever, fall in oxygen' saturation, abnormal appearance on chest radiography, and reduction in respiratory function) on the 13th, 18th, 24th, and 34th postoperative days. The diagnosis was confirmed at bronchoscopy, when histological examination of transbronchial lung biopsy specimens showed perivascular cuffing with mononuclear cells. He was successfully treated on each occasion by pulsed doses of intravenous methylprednisolone (1 g intravenously thrice daily). As appropriate to the antibiotic sensitivities of the pseudomonas isolated from his sputum immediately before surgery, he was started on ciprofloxacin and imipenem for the first 10 postoperative days together with -inhaled colistin sulphate. On the 10th postoperative day Candida albicans was isolated from his sputum and, in the absence of radiological change, he was successfully treated with nebulised amphotericin. He required intravenous antibiotics for pseudomonal respiratory infections three times and for Staphylococcus aureus pneumonia once in the first two postoperative months. At the beginning of the third postoperative month he developed a fever of 40°C associated with hypoxia, and diffuse interstitial shadowing was visible on a chest radiograph. Transbronchial lung biopsy confirmed the diagnosis of cytomegalovirus pneumonitis (fig 2), which was successfully treated with a combination of intravenous ganciclovir and hyperimmune globulin to cytomegalo-
Other postoperative complications encountered prolonged intubation and ventilation for 11 weeks, which necessitated the insertion of a tracheostomy tube; a left haemothorax requiring the insertion of a chest drain; systolic hypertension requiring treatment with nifedipine; diffuse peripheral oedema secondary to hypoalbuminaemia; and abnormal liver function probably secondary to azathioprine treatment -liver function returned to normal after temporary withdrawal of the drug. The man was discharged from hospital three months after surgery. However one month later he became acutely ill while away from home and on arrival at Harefield Hospital he developed a cardiorespiratory arrest. He was resuscitated and was hypotensive, FIG 1-Chest radiograph before (left) and three months after (right) transplantation. Before tra npiantation clinically septic, and in acute renal failure. He required typical features of cystic fibrosis are visible with bronchial wall thickening and overinflated lu'ngs. There is inotropic support, replacement fluid therapy, and evidence ofprevious thoracotomies for bilateral pleurodesis haemofiltration. A bronchoscopy was done and the were:
BMJ VOLUME 304
28 MARCH 1992
835
A~~~~~~~~
FIG 2-Lung biopsy specimen staned with haematoxyln and eosn showing multiple cytomegalovirus inclusion bodies (arrows)
bronchial tree was found to be full of secretions, from which Streptococcus pneumoniae was isolated. He was treated with intravenous benzylpenicillin and given azathioprine and hydrocortisone for immunosuppression. He responded well to treatment and was discharged from hospital two weeks later. Three years after the transplant operation he was back at work and took regular exercise: walking, cycling, and swimming. A radiograph showed that his chest was clear (fig 1 (right)); his forced expiratory volume was 3 1 and forced vital capacity was 3-5 1. His immunosuppressive regimen was cyclosporin 8 mg/kg! day, azathioprine 100 mg daily, and prednisolone 5 mg daily. Comments Postoperative complications of heart-lung transplantation include acute rejection, infection, renal failure, multiorgan failure, seizures, lymphoproliferative disorders, and bronchiolitis obliterans. Patients with cystic-fibrosis may also develop other problems. Firstly, they may have malabsorption of cyclosporin A and thus require higher doses. Secondly, they are prone to pseudomonal respiratory infections. Dual antipseudomonal antibiotic treatment is given intravenously for the first 10 postoperative days together with long term inhaled colistin sulphate. Thirdly, liver disease may preclude patients from taking azathioprine. Fourthly, often patients cannot quickly start eating. In such patients we use an elemental diet given nasogastrically or through a gastrostomy tube. Fifthly, they may have meconium ileus equivalent, which should be treated by Nacetylcysteine. Sixthly, hyponatraemia in these patients can be exacerbated by diuretics. Lastly, patients may have diabetes mellitus and require an insulin infusion over the operative and immediate postoperative period. Heart-lung transplantation started in the early 1980s and was initially confined to patients with pulmonary vascular conditions. We were particularly worried about treating patients who had pulmonary infection and there was also concern that cystic fibrosis might recur in the transplanted lung. We have performed 275 heart-lung transplant operations in our unit, of which 79 were for cystic fibrosis. Heart-lung transplantation is the most common operation, although bilateral single lung transplantation is another option. One of the critical considerations in deciding on the operation is the blood supply to the bifurcation of the trachea. During the operation we only anastomose the pul-
836
monary artery, the pulmonary veins, and the airways and anastomosis of the bronchial arteries until recently has not been attempted. In transplanting the heartlung block there is a good blood supply from the coronary arteries to the area ofthe tracheal anastomosis, which usually heals well. Transplantation of both lungs without the heart is often associated with airway anastomotic problems. Our patient had several high risk factors-namely ventilation, bilateral pleurodesis, diabetes, and steroid treatment. We have now shown that the overall survival of patients with supposed high risk factors can be very encouraging.5 The overall survival to one year of our first 52 patients with cystic fibrosis was 69%. In most patients the lung function has been well maintained for over three years. Nevertheless, obliterative bronchiolitis is a risk for patients after heart-lung or single lung transplantation.
Discussion EWFWA: What is the relation between preoperative and postoperative pseudomonal types? MEH: No clear relation has so far been shown, but we are currently studying this using DNA typing. There does, however, seem to be a relation between the type of pseudomonas in the patient's upper airways and the pseudomonas found in the transplanted lung. PJB: What do you think of the new immunosuppressive compound FK506? MHY: It is a promising drug and most of the early work has been done on patients receiving liver transplants. We await developments. DMD: How long does the transplanted lung retain its genetic identity? MHY: Some studies on the heart and some on the lung show that the HLA identity of the cardiac monocytes and endothelium remains that of the donor, five years after transplantation. ABK: Have you considered using cyclosporin sparing strategies or inhaled cyclosporin? MHY: Routinely we use azathioprine together with cyclosporin. We avoid corticosteroids whenever possible and reserve them for treating episodes of rejection. We also use monoclonal antibodies to T lymphocytes, but these do not seem as promising as previously thought. We have no experience with inhaled cyclosporin. ANT: What are the causes of obliterative bronchiolitis? MHY: There is evidence that it is a manifestation of rejection and that it is the counterpart of the accelerated coronary artery sclerosis seen in recipients of heart transplants or the arterial disease seen in recipients of kidney and liver transplants. DMG: What are the chances of removing both lungs at once and then transplanting a single lung, and what about using animal organs? MHY: I would be very worried about leaving a pneumonectomy space in an immunosuppressed patient, which would be a source of infection and empyema. As far as animal organs are concerned more work needs to be done. I British Paediatric Association Working Party on Cystic Fibrosis. Cystic fibrosis in the United Kingdom 1977-85: an improving picture. BMJ 1988;297:
1599-602. 2 Penketh ARL, Wise A, Mearns MP, Hodson ME, Batten JC. Cystic fibrosis in adolescents and adults. Thorax 1987;42:526-32. 3 Scott J, Hunter J, Stewart S, Higenbottam T, Hodson M, Penketh A, et al. Heart-lung transplantation for cystic fibrosis. Lancet 1988;ii: 192-4. 4 Yacoub MH, Banner NR, Khaghani A, Fitzgerald M, Madden B, Tsang V, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Transplant 1990;9:459-67. 5 Tsang V, Madden BP, Hodson ME, Yacoub ME. Heart-lung transplantation for cystic fibrosis. Pediatr Pulmonol 1990;supplS:256.
BMJ
VOLUME
304
28
MARCH
1992
