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Early experience with sequential bilateral lung transplantation
Early experience with sequential bilateral lung transplantation We performed 20 sequential bilateral lung transplantations in 19 consecutive patients from April 1990 to May 1992. Perioperative mortality was low (2 patients). One-year actuarial survival was 70 %. All survivors had normal blood oxygen tension (82 mm Hg, mean) while breathing room air and continuing improvement of pulmonary function. Bronchial dehiscence did not occur. Stents were implanted in 7 patients to control bronchial stenosis. Aggressive treatment of graft rejection has been effective in preventing obliterative bronchiolitis. (J THORAC CARDIOVASC SURG 1993;106:463-5)
M. Grimm, MD,a W. Wisser, MD,a A. End, MD,a M. Hiesmayr, MD,b O. C. Burghuber MD,c H. Ringl, MS,a A. Stift, MS,a D. Oturanlar, MD,a G. Wollenek, MD,a G. Grimm, MD,d E. WoIner, MD,a and W. Klepetko, MD,a Vienna, Austria
Bilateral sequential lung transplantation has recently become a routine procedure in the treatment of patients with end-stage lung disease. 1, 2 It is performed in several centers in the United States and Europe. We report clinical experience, outcome, and complications of the bilaterallung transplant program at the University of Vienna. Patients and methods Patients. Twenty bilateral sequential lung transplantations were performed in 19 selected consecutive patients at the University of Vienna between April 1990 and May 1992. Eight patients had emphysema, 2 cystic fibrosis, 3 bronchiectasis, 3 pulmonary fibrosis, I histiocytosis X, I Eisenmenger's complex with atrial septal defect, I primary pulmonary hypertension, and I bilateral retransplantation for bronchomalacia. Bilateral instead of single lung transplantation was performed because of chronic intrapulmonary infection (n = 10), smaller-sized donor lungs (n = 5), large bilateral bullae (n = 2), preexisting pulmonary hypertension (to overcome problems of posttransplantation pulmonary overflow, n = 2), and retransplantation because of bilateral bronchomalacia (n = I). Operative procedure. Harvest of donor organs and bilateral Fromthe Second Departmentof Surgery"; the Departmentof Anaesthesiology, Division of Pulmonology"; the Fourth Department of Internal Medicine': and the Division of Intensive Care Medicine, Fourth Department of Internal Medicined; University of Vienna, Vienna, Austria. Received for publication July 7, 1992. Accepted for publication Nov. 3,1992. Address for reprints: W. Klepetko, MD, Second Department of Surgery, University of Vienna, Spitalgasse 23, A-I090 Vienna, Austria. Copyright © 1993 by Mosby-Year Book, Inc. 0022-5223/93 $1.00+.10 12/1/44181
sequential lung transplantation were performed as described recently. I, 2 In patients I to 6 bronchial anastomoses were performed by means of a telescoping technique (the donor bronchus was inserted into the recipient bronchus and sewn with 3-0 Vicryl single stitches*); in patients 7 to 19 anastomoses were performed in end-to-end fashion (4-0 PDS running suture* was used at the membraneous portion and single stitches at the cartilaginous portion). Immunosuppression and prophylactic therapy. Immunosuppression was based on standard triple therapy with steroids (1000 mg methylprednisolone during the operation and prednisolone 2 mg/kg per day, which was tapered to 0.2 mg/kg per day during 2 months), azathioprine (2 mg/kg per day), and cydosporine (200 to 400 ng/rnl target level, high-performance liquid chromatography). Antithymocyte globulin (10 mg/kg per day) was given 3 days after the operation. Cytomegalovirus hyperirnmunoglobulin (2 ml/kg) was given immediately before transplantation, on postoperative days 1,2,7, 14, and 21, and 3 months after transplantation. Standard therapy for graft rejection was a 3-day bolus course of methylprednisolone (1000 mg) given intravenously. In episodes of steroid-refractory rejections, OKT3 (5 rug/day for 10 days in 2 patients) or ATG (10 rug/kg per day for 10 days in I patient) was used. Routine transbronchial biopsy was performed 2 and 8 weeks after transplantation, and further biopsies were done every 3 months. Statistical analysis. Time-related survival was calculated by the method of Kaplan and Meier.' For comparison of paired data, Student's t test was used.
Results One-year actuarial survival was 70% (Fig. I). Fifteen patients are alive and well up to 18 months after transplantation. Two patients died in the perioperative *Ethicon, Inc., Somerville, N.J.
463
The Journal of Thoracic and Cardiovascular Surgery September 1993
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Fig. 1. Kaplan-Meier analysis of patient survival after bilateral sequential lung transplantation. period of multiorgan failure, I patient died of bleeding from a spontaneous arteriobronchial fistula 5 months after transplantation, and I patient died of erosionbleeding during laser ablation of a bronchial stenosis. Blood oxygen tension in all survivors improved after transplantation (p < 0.05 versus the preoperative value) and none required supplemental oxygen (Fig. 2). Pulmonary function parameters improved continuously (p < 0.05) and reached the normal range within I year (Fig. 3). For prevention of bronchial stenosis, 9 silicone stents were implanted in 7 patients. Mean implantation time of the stents was 3.4 months. Bronchial dehiscence did not occur. One to 2 months after transplantation, bronchial stenosis had developedin 5 of 8 anastomoses performed by the telescoping technique but in only 3 of 28 by the end-to-end technique (p < 0.05). The airway complication rate was higher in transplantations 1 to 10 (30%) than in transplantations 11 to 20 (10%). At present, only I stent is still place; all others have been removed. Over the total follow-up period of 149 months, 39 episodes of graft rejection were observed (0.26 episodesper follow-up month). Institution of antirejection treatment was based on clinical symptoms such as a decrease of bloodgasesor pulmonary functionor the presenceof fever or infiltrates (chest roentgenogram) in 21 occasions, on clinicalsymptomsand transbronchial biopsyin 10,and on transbronchial biopsy without clinical symptoms in 8 occasions. Notably, in 2 of 3 patients with severe rejections treated with OKT3 or ATG, varicellapneumonia (1 patient) and monoclonal B-cell lymphoma (I patient) occurred. Symptomatic cytomegalovirus infection occurred in 4 patients (mild illnessin 2 and severehistologically proved pneumonitis in 2 patients). All patients with cytomegalo-
25
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pre-op n=19
·1 month n=14
6 months n=13
> 1 year n=4
Fig. 2. Blood gas analysis after bilateral sequential lung transplantation. Solid bars indicate arterial oxygen tension and cross-hatched bars indicate arterial carbon dioxide tension. Asterisks indicate significance as compared with preoperative values (p < 0.05). virus infectionswere successfully treated with ganciclovir (10 rug/kg per day for 14 days) and CMV-hyperimmunoglobulin (2 ml/kg). Severe bacterial infections were observed in 2 patients. Discussion
A l-year actuarial survivalof 70%indicatesthat bilateral sequential lung transplantation is an appropriate procedure for the treatment of selected patients with end-stage lung disease. We selected bilateral instead of single lung transplantation" in patients with chronicintrapulmonary infectious diseasesas wellas in younger patients or in case of smaller-sized donor lungs to achieve a maximal functional recovery.lMarked disturbances of postoperativerecovery such as reperfusion edema, severe rejection, or infection can be handled more simply in critically ill patients after bilateral than after single lung transplantation. For this reason we switched from single to bilateral transplantation in patients with pulmonary hypertension to avoid pulmonary overflow. In our experience the extent of bilateral as compared with single lung transplantation crucially aggravates postoperative recovery. Therefore the bilateral procedure requires careful patient selection. Since 3 of the 4 patients who died had progressive pulmonarycachexia and immobility,these patients had to be excluded from a bilateral procedure. The survivors of bilateral lung transplantation have normal pulmonary function and blood gas values. We found only a slight reduction of the aerobic exercise capacity (data not shown), probably as a result of longterm preoperative immobility. All patients except 2 were
The Journal of Thoracic and Cardiovascular Surgery Volume 106. Number 3
discharged from the hospital within 35 days and are living at home with a good quality of life. In the early phase of the program the rate of bronchial stenosis requiring stenting was high although the rate of long-term complications was low. Most stents could be removed from stabilized airways. The prevalence of bronchial stenosis could be reduced in the following patients by switching from telescopic (without figure-ofeight sutures as performed by Calhoon and associates") to end-to-end anastomosis along with improvement of surgical technique. Decision for antirejection therapy in the early postoperative period was based primarily on clinical symptoms. Later on, transbronchial biopsy became more important because histologic findings are effective in either diagnosis of cytomegalovirus infection or detection of clinically asymptomatic, ongoing rejection."? Our strategy of aggressive antirejection treatment even in symptom-free patients has resulted in continuous improvement of pulmonary function and effective prevention of obliterative bronchiolitis to this point.!? Nevertheless, repeated steroid courses or the use of OKT3 11 can be associated with infectious or lymphoproliferative events. To minimize the prevalence and severity of rejection episodes, we have now changed our regimen by extending prophylactic A TG therapy from 3 to 7 days. Sequential bilateral lung transplantation offers a therapeutic strategy with excellent functional results and an acceptable mortality rate for selected noncachectic patients with end-stage pulmonary diseases. REFERENCES 1. Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulock EP. Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thorac Surg 1990;49:785-91. 2. Bisson A, Bonette P. A new technique for double lung transplantation: "bilateral single lung" transplantation. J THORAC CARDIOVASC SURG 1992;103:40-6. 3. Kaplan EI, Meier P. Nonparametric estimations from incompleteobservation. J Am Stat Assoc 1958;53:457-81. 4. Starnes VA, LewistonN, Theodore J, et al. Cystic fibrosis: target populationfor lung transplantation in North America in the 1990s. J THoRAc CARDIOVASC SURG 1992; 103:1008-14. 5. Patterson GA, Maurer JR, Williams TJ, et al. Comparison
Grimm et al. 4 6 5
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Fig. 3. Pulmonary function after bilateral sequential lung transplantation. Solid bars indicate vital capacity, crosshatched bars indicate forcedexpiratory volumein 1second,and dotted bars indicate total lung capacity. Asterisks indicate significance as compared with preoperative values (p < 0.05). In the preoperativepulmonary function tests 1 patient was excluded because the patient was completely ventilator dependent. of outcomes of double and single lung transplantation for obstructive lung disease. J THORAC CARDIOVASC SURG 1991;101:623-32. 6. Calhoon JH, Grover FL, Gibbons WJ, et al. Single lung transplantation: alternative indications and technique. J THORAC CARDIOVASC SURG 1991;101:816-25. 7. Steinhoff G, Behrend M, Wagner TOF, Hopper MH, Haverich A. Early diagnosis and effective treatment of pulmonary CMV infection after lung transplantation. J Heart Lung Transplant 1991;10:9-14. 8. Duncan AJ, Dummer JS, Paradis IL, et al. Cytomegalovirus infection and survivalin lung transplant recipients. J Heart Lung Transplant 1991;10:638-46. 9. Yousem SA, Berry GJ, Brunt EM, et al. A working formulation for the standardization of nomenclature in the diagnosisof heart and lung rejection: lung rejection study group. J Heart Lung Transplant 1990;9:593-601. 1O.LoCicero J III, Robinson PG, Fisher M. Chronic rejection in single lung transplantation manifested by obliterative bronchiolitis. J THoRAcCARDIOVASC SURG 1990;99:105962. 11. Armitage JM, KormosRL, Stuart RS, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: Ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991;10:877-87.
M. Grimm, MD,a W. Wisser, MD,a A. End, MD,a M. Hiesmayr, MD,b O. C. Burghuber MD,c H. Ringl, MS,a A. Stift, MS,a D. Oturanlar, MD,a G. Wollenek, MD,a G. Grimm, MD,d E. WoIner, MD,a and W. Klepetko, MD,a Vienna, Austria
Bilateral sequential lung transplantation has recently become a routine procedure in the treatment of patients with end-stage lung disease. 1, 2 It is performed in several centers in the United States and Europe. We report clinical experience, outcome, and complications of the bilaterallung transplant program at the University of Vienna. Patients and methods Patients. Twenty bilateral sequential lung transplantations were performed in 19 selected consecutive patients at the University of Vienna between April 1990 and May 1992. Eight patients had emphysema, 2 cystic fibrosis, 3 bronchiectasis, 3 pulmonary fibrosis, I histiocytosis X, I Eisenmenger's complex with atrial septal defect, I primary pulmonary hypertension, and I bilateral retransplantation for bronchomalacia. Bilateral instead of single lung transplantation was performed because of chronic intrapulmonary infection (n = 10), smaller-sized donor lungs (n = 5), large bilateral bullae (n = 2), preexisting pulmonary hypertension (to overcome problems of posttransplantation pulmonary overflow, n = 2), and retransplantation because of bilateral bronchomalacia (n = I). Operative procedure. Harvest of donor organs and bilateral Fromthe Second Departmentof Surgery"; the Departmentof Anaesthesiology, Division of Pulmonology"; the Fourth Department of Internal Medicine': and the Division of Intensive Care Medicine, Fourth Department of Internal Medicined; University of Vienna, Vienna, Austria. Received for publication July 7, 1992. Accepted for publication Nov. 3,1992. Address for reprints: W. Klepetko, MD, Second Department of Surgery, University of Vienna, Spitalgasse 23, A-I090 Vienna, Austria. Copyright © 1993 by Mosby-Year Book, Inc. 0022-5223/93 $1.00+.10 12/1/44181
sequential lung transplantation were performed as described recently. I, 2 In patients I to 6 bronchial anastomoses were performed by means of a telescoping technique (the donor bronchus was inserted into the recipient bronchus and sewn with 3-0 Vicryl single stitches*); in patients 7 to 19 anastomoses were performed in end-to-end fashion (4-0 PDS running suture* was used at the membraneous portion and single stitches at the cartilaginous portion). Immunosuppression and prophylactic therapy. Immunosuppression was based on standard triple therapy with steroids (1000 mg methylprednisolone during the operation and prednisolone 2 mg/kg per day, which was tapered to 0.2 mg/kg per day during 2 months), azathioprine (2 mg/kg per day), and cydosporine (200 to 400 ng/rnl target level, high-performance liquid chromatography). Antithymocyte globulin (10 mg/kg per day) was given 3 days after the operation. Cytomegalovirus hyperirnmunoglobulin (2 ml/kg) was given immediately before transplantation, on postoperative days 1,2,7, 14, and 21, and 3 months after transplantation. Standard therapy for graft rejection was a 3-day bolus course of methylprednisolone (1000 mg) given intravenously. In episodes of steroid-refractory rejections, OKT3 (5 rug/day for 10 days in 2 patients) or ATG (10 rug/kg per day for 10 days in I patient) was used. Routine transbronchial biopsy was performed 2 and 8 weeks after transplantation, and further biopsies were done every 3 months. Statistical analysis. Time-related survival was calculated by the method of Kaplan and Meier.' For comparison of paired data, Student's t test was used.
Results One-year actuarial survival was 70% (Fig. I). Fifteen patients are alive and well up to 18 months after transplantation. Two patients died in the perioperative *Ethicon, Inc., Somerville, N.J.
463
The Journal of Thoracic and Cardiovascular Surgery September 1993
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Fig. 1. Kaplan-Meier analysis of patient survival after bilateral sequential lung transplantation. period of multiorgan failure, I patient died of bleeding from a spontaneous arteriobronchial fistula 5 months after transplantation, and I patient died of erosionbleeding during laser ablation of a bronchial stenosis. Blood oxygen tension in all survivors improved after transplantation (p < 0.05 versus the preoperative value) and none required supplemental oxygen (Fig. 2). Pulmonary function parameters improved continuously (p < 0.05) and reached the normal range within I year (Fig. 3). For prevention of bronchial stenosis, 9 silicone stents were implanted in 7 patients. Mean implantation time of the stents was 3.4 months. Bronchial dehiscence did not occur. One to 2 months after transplantation, bronchial stenosis had developedin 5 of 8 anastomoses performed by the telescoping technique but in only 3 of 28 by the end-to-end technique (p < 0.05). The airway complication rate was higher in transplantations 1 to 10 (30%) than in transplantations 11 to 20 (10%). At present, only I stent is still place; all others have been removed. Over the total follow-up period of 149 months, 39 episodes of graft rejection were observed (0.26 episodesper follow-up month). Institution of antirejection treatment was based on clinical symptoms such as a decrease of bloodgasesor pulmonary functionor the presenceof fever or infiltrates (chest roentgenogram) in 21 occasions, on clinicalsymptomsand transbronchial biopsyin 10,and on transbronchial biopsy without clinical symptoms in 8 occasions. Notably, in 2 of 3 patients with severe rejections treated with OKT3 or ATG, varicellapneumonia (1 patient) and monoclonal B-cell lymphoma (I patient) occurred. Symptomatic cytomegalovirus infection occurred in 4 patients (mild illnessin 2 and severehistologically proved pneumonitis in 2 patients). All patients with cytomegalo-
25
OJ
+-"
(0
0
pre-op n=19
·1 month n=14
6 months n=13
> 1 year n=4
Fig. 2. Blood gas analysis after bilateral sequential lung transplantation. Solid bars indicate arterial oxygen tension and cross-hatched bars indicate arterial carbon dioxide tension. Asterisks indicate significance as compared with preoperative values (p < 0.05). virus infectionswere successfully treated with ganciclovir (10 rug/kg per day for 14 days) and CMV-hyperimmunoglobulin (2 ml/kg). Severe bacterial infections were observed in 2 patients. Discussion
A l-year actuarial survivalof 70%indicatesthat bilateral sequential lung transplantation is an appropriate procedure for the treatment of selected patients with end-stage lung disease. We selected bilateral instead of single lung transplantation" in patients with chronicintrapulmonary infectious diseasesas wellas in younger patients or in case of smaller-sized donor lungs to achieve a maximal functional recovery.lMarked disturbances of postoperativerecovery such as reperfusion edema, severe rejection, or infection can be handled more simply in critically ill patients after bilateral than after single lung transplantation. For this reason we switched from single to bilateral transplantation in patients with pulmonary hypertension to avoid pulmonary overflow. In our experience the extent of bilateral as compared with single lung transplantation crucially aggravates postoperative recovery. Therefore the bilateral procedure requires careful patient selection. Since 3 of the 4 patients who died had progressive pulmonarycachexia and immobility,these patients had to be excluded from a bilateral procedure. The survivors of bilateral lung transplantation have normal pulmonary function and blood gas values. We found only a slight reduction of the aerobic exercise capacity (data not shown), probably as a result of longterm preoperative immobility. All patients except 2 were
The Journal of Thoracic and Cardiovascular Surgery Volume 106. Number 3
discharged from the hospital within 35 days and are living at home with a good quality of life. In the early phase of the program the rate of bronchial stenosis requiring stenting was high although the rate of long-term complications was low. Most stents could be removed from stabilized airways. The prevalence of bronchial stenosis could be reduced in the following patients by switching from telescopic (without figure-ofeight sutures as performed by Calhoon and associates") to end-to-end anastomosis along with improvement of surgical technique. Decision for antirejection therapy in the early postoperative period was based primarily on clinical symptoms. Later on, transbronchial biopsy became more important because histologic findings are effective in either diagnosis of cytomegalovirus infection or detection of clinically asymptomatic, ongoing rejection."? Our strategy of aggressive antirejection treatment even in symptom-free patients has resulted in continuous improvement of pulmonary function and effective prevention of obliterative bronchiolitis to this point.!? Nevertheless, repeated steroid courses or the use of OKT3 11 can be associated with infectious or lymphoproliferative events. To minimize the prevalence and severity of rejection episodes, we have now changed our regimen by extending prophylactic A TG therapy from 3 to 7 days. Sequential bilateral lung transplantation offers a therapeutic strategy with excellent functional results and an acceptable mortality rate for selected noncachectic patients with end-stage pulmonary diseases. REFERENCES 1. Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulock EP. Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thorac Surg 1990;49:785-91. 2. Bisson A, Bonette P. A new technique for double lung transplantation: "bilateral single lung" transplantation. J THORAC CARDIOVASC SURG 1992;103:40-6. 3. Kaplan EI, Meier P. Nonparametric estimations from incompleteobservation. J Am Stat Assoc 1958;53:457-81. 4. Starnes VA, LewistonN, Theodore J, et al. Cystic fibrosis: target populationfor lung transplantation in North America in the 1990s. J THoRAc CARDIOVASC SURG 1992; 103:1008-14. 5. Patterson GA, Maurer JR, Williams TJ, et al. Comparison
Grimm et al. 4 6 5
150 (J) (l)
:J
to
> 1)
100
(l) +-'
u -0 (l)
Q
50
et-
0
'
o
pre-op n=18
1 month n=13
6 months n=11
> 1 year n=4
Fig. 3. Pulmonary function after bilateral sequential lung transplantation. Solid bars indicate vital capacity, crosshatched bars indicate forcedexpiratory volumein 1second,and dotted bars indicate total lung capacity. Asterisks indicate significance as compared with preoperative values (p < 0.05). In the preoperativepulmonary function tests 1 patient was excluded because the patient was completely ventilator dependent. of outcomes of double and single lung transplantation for obstructive lung disease. J THORAC CARDIOVASC SURG 1991;101:623-32. 6. Calhoon JH, Grover FL, Gibbons WJ, et al. Single lung transplantation: alternative indications and technique. J THORAC CARDIOVASC SURG 1991;101:816-25. 7. Steinhoff G, Behrend M, Wagner TOF, Hopper MH, Haverich A. Early diagnosis and effective treatment of pulmonary CMV infection after lung transplantation. J Heart Lung Transplant 1991;10:9-14. 8. Duncan AJ, Dummer JS, Paradis IL, et al. Cytomegalovirus infection and survivalin lung transplant recipients. J Heart Lung Transplant 1991;10:638-46. 9. Yousem SA, Berry GJ, Brunt EM, et al. A working formulation for the standardization of nomenclature in the diagnosisof heart and lung rejection: lung rejection study group. J Heart Lung Transplant 1990;9:593-601. 1O.LoCicero J III, Robinson PG, Fisher M. Chronic rejection in single lung transplantation manifested by obliterative bronchiolitis. J THoRAcCARDIOVASC SURG 1990;99:105962. 11. Armitage JM, KormosRL, Stuart RS, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: Ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991;10:877-87.