- Email: [email protected]
Improved survival after heart-lung transplantation
J THoRAc CARDIOVASC SURG 1990;99:54-60
Improved survival after heart-lung transplantation sixty-two patients underwent 65 heart-lung transplant operations before April 1989. Thirty of these patients (operated on March 1981 to February 1986) were given cyclosporine and prednisone for immunosuppression. These 30 patients (group 1) are compared with the 32 most recent patients (group 2) treated with cyclosporine, prednisone, and azathioprine. Patient characteristics (group 1 versus group 2) were sinillar including age (mean 32 versus 26 years)and indication for operation (51% versus 38%, primary pulmonary hypertension; 46 % versus 45 %, Eisenmenger complex; 3 % versus 17 %, other). The perioperative (in-hospital) mortality rate was 35 % in group 1 versus 16 % in group 2. Obliterative bronchiolitis developed in 12 (63%) of 19 hospital survivors in group 1 from 2 months to 49 months postoperatively (mean 12 months). This complication bas developed in five (20%) of the 25 hospital survivors in group 2 from 3 to 13 months postoperatively (mean 8 months~ Overall, 24 of the 30 patients in group 1 died (infection in eight, obliterative bronchiolitis in five, graft coronary artery disease in two, other causes in nine). Eight of the 32 patients in group 2 died (infection in six, other causes in two), Survival rates for group 1 patients were 60% at 1 year, 50% at 2 years, 43% at 3 years, and 25% at 5 years. Survival rates for group 2 patients were 73% at 1 year, 13% at 2 years, and 65% at 3 years (p < 0.05). When group 2 patients were compared with 134 patients undergoing heart transplantation during the same time period, there was no difference in survival. Routine bron~hoscopic surveillance in the more recent group of patients bas led to the earlier detection of rejection and infection. In combination with decreased perioperative mortality and augmented immunosuppression, this had led to improved survival in our more recent heart-lung transplant recipients. In addition, the earlier recognition of infection and rejection has led to a decrease in severity of obliterative bronchiolitis.
Patrick M. McCarthy, MD (by invitation), Vaughn A. Starnes, MD (by invitation), James Theodore, MD (by invitation), Edward B. Stinson, MD, Philip E. Oyer, MD, and Norman E. Shumway, MD, Stanford, Calif.
h e successful introduction of cyclosporine in heart transplantation and encouraging results with heart-lung transplantation in primates-? preceded the initiation of clinicalheart-lung transplantation at Stanford in 1981.3 Since then many changeshave evolved regarding patient selection, donor organ preservation, postoperative immunosuppression, recognition and treatment of rejectionand infection, and the occurrenceand management oflate sequelae such as obliterativebronchiolitis (OB). Although cardiac transplantation is a more established therapy, From the Departments of Cardiovascular Surgery and Medicine, Stanford University School of Medicine, Stanford, Calif.
much progress has been made with heart-lung transplantation and results are continuingto improve. This report summarizesour entireclinicalexperience withheart-lung transplantation.To emphasizethe progress that has taken place, we divided the experience into two groups on the basis of immunosuppression regimens. The early experience used primarilycyclosporine with prednisone for immunosuppression, and the more recent group (since March 1986) utilizedcyclosporine, prednisone, and azathioprine. The division into twogroups is somewhatarbitrary becauseother changesin management haveevolved in additionto immunosuppression changes,and thesewill also be reviewed.
Read at the Sixty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass., May 8-10,1989.
Patients and methods
Address for reprints: Vaughn A. Starnes, MD, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, cA. 94305.
12/6/16329
54
Sixty-two patients received 65 heart-lung grafts from March 9,1981, until April I, 1989. The clinical characteristics of these patients are summarized in Table I according to two groups. Group 1 comprised patients whose transplant operations were
Volume 99
Heart-lung transplantation
Number 1 January 1990
Table II. In-hospital deaths
Table I. Patient characteristics No. of patients No. H-L Tx Age" (yr) Mean Range Sex, M:F Indications PH
CHD
CF OB Rejection
Group]
Group 2
Tota]
30 31
32 34
62 65
32 22-45 18:12
26 2-44 11:21
29:33
16 14
13 IS
29 29
4 I I
4
I
Postop. day
o I
o o
55
4 II
2 I
H-L Tx, Heart-lung transplants; PH, pulmonary hypertension; CHD, congenital heart disease (Eisenmenger's syndrome); CF, cystic fibrosis; OB, obliterative bronchiolitis; ·Median, 29.3 years.
13 16 20 20 23 33 38 22 37 51
57 99
performed from March 1981 to February 1986 and group 2, from March 1986 to March 1989. Recipients were all disabled by end-stage pulmonary disease and many had severe right heart failure. Patients with renal or primary hepatic disease, diabetes, autoimmune disease, or malignancy were excluded. Twenty-nine patients with congenital heart disease had Eisenmenger physiology. Twenty-seven patients had primary pulmonary hypertension. One patient had pulmonary hypertension resulting from bronchiectasis and another from cardiomyopathy. Four patients with cystic fibrosis recently underwent transplantation. Two patients required repeat transplantation after the development of severe deterioration from OB. One 2-year-old child required repeat transplantation at 1 month because of severe rejection with adenovirus pneumonia. Another patient had failure of the donor heart at implantation. He was supported with an intraaortic balloon pump until a new heart could be transplanted into the graft 24 hours later. The allograft donor selection was particularly stringent." All but one met the following donor criteria: arterial oxygen tension greater than 90 mm Hg on 40% inspired oxygen; peak inspiratory pressure less than 30 em H 20 during respiratory support, with a tidal volume of 12 to 15 ml/kg; and a clear chest film. Donor size was matched to the recipient by body size and thoracic dimensions. The recipient was selected to be the same size or slightly larger than the donor. A Gram stain and tracheal culture were routinely performed on the donor trachea. The first 32 transplants were performed after transport of the donor to Stanford for local procurement of the grafts. For later transplants the organs were preserved with prostaglandin E 1 (PGE I ) as a pulmonary vasodilator, subsequent copious pulmonary artery flush with modified Euro-Collins solution at 4 0 C, and transport with topical cooling."? The most recent 33 transplants were performed in this manner with 21 of the grafts harvested at a distant hospital. The graft implantation operation has been described before.S 6,10 Of particular note, the tracheal anastomosis was performed just above the carina with a continuous suture of 3-0 polypropylene. Omentum was never used to reinforce the suture line. More recent operations have been performed with careful
Cause of death Group]
Pulmonarygraft failure Bleeding complications Bleeding complications Infection (pneumonia) Bleeding complications Bleeding complications Infection (aortic suture line) MOF; brain death MOF; brain death Infection (pneumonia) Infection (mediastinitis) Group 2
Infection? (aortic suture line) MOF; brain death Infection (pneumonia) Infection (pneumonia) Infection (pneumonia)
MOF, Multiple organ failure.
reapproximation of the recipient peritracheal tissue to the donor peritracheal/pericardial tissue around the anastomosis. Two of the recipient hearts (one patient with cystic fibrosis and one with bronchiectasis) were harvested and used for "domino" transplants in heart recipients. In group I, cyclosporine was administered to maintain the radioimmunoassay cyclosporine level between 150 and 250 tig] ml.'! Patients received rabbit antithymocyte globulin for the initial 3 days and azathioprine (1.5 mg/kg/day) for the first 2 weeks. At 2 weeks azathioprine was stopped and 5 mg prednisone twice a day was begun. Maintenance therapy consisted of cyclosporine and prednisone.. For group II patients, cyclosporine was given to maintain a level of 200 to 300 ng/rnl for the first 30 days and 100 to 200 ng/rnl thereafter. Methylprednisolone sodium succinate (SoluMedrol) was given the first 24 hours postoperatively and prednisone was begun on the fourteenth postoperative day (0.4 tug] kg/day initially and then tapered to 0.2 mg/kg/day by discharge). Azathioprine was given as a 4 rug/kg loading dose and then as a maintenance dose of 2 mg/kg/day, The most recent 16 patients received OKTJ (Ortho Diagnostic Systems, Inc., Raritan, N.J.) at 5 mg/kg/day for the first 10 days. Maintenance therapy consisted of cyclosporine, prednisone, and azathioprine. Surveillance for rejection and infection has markedly changed during the clinical program. Initially, endomyocardial biopsy alone was performed weekly while the patient remained in the hospital and as needed for clinical evidence of rejection. I I This practice continues currently, but in addition, after the recognition of asynchronous heart and lung rejection.l- 13 isolated pulmonary rejection has been more carefully evaluated. Although bronchoscopy was used only occasionally in group 1,14 it has become a weekly in-hospital surveillance procedure in the most recent 16 patients'> and as needed for clinical indications of rejection. At bronchoscopy, both transbronchial biopsy and bronchoalveolar lavage were performed. Pulmonary function tests with arterial blood gases were ob-
The Journal of Thoracic and Cardiovascular Surgery
56 McCarthy et al.
Table III. Late deaths Postop. month
Causeofdeath Group 1
11 14 15 15
27 35
47 52 53 55 57
63 73
Obliterative bronchiolitis Obliterative bronchiolitis Graft atherosclerosis Infection (pneumonia) Obliterative bronchiolitis Obliterative bronchiolitis Obliterative bronchiolitis Graft atherosclerosis Infection (pneumonia) (Post redo H-L Tx-see group 2) Infection (pneumonia) Intraabdominal bleeding after trauma Infection (pneumonia) re H-L Tx
Group 2 5 7 II
26
Cerebrovascular accident Infection (pneumonia) Graft atherosclerosis Infection (pancreatitis)
tained after extubation, weekly beginning 2 weeks after transplantation,biweekly after 2 months,and at leastevery2 months during the long-termfollow-up. They wereobtainedmoreoften as clinical need dictated. Current clinical follow-up was obtained from the patientsor from their referringphysicians until April I, 1989.
Results In group 1 there was one intraoperative death resulting from acute pulmonary failure with a graft from a donor with borderline blood gas values (see Table II). Four patients died from 1 to 16 days postoperatively of complications related to excessive bleeding. Four other patients died from 11 to 38 days postoperatively of infection. Two of these patients had pneumonia with sepsis. Another patient (who had received a heart transplant for cardiac failure of the heart-lung graft) died of Candida mediastinitis. One other patient bled massively from the aortic suture line 20 days postoperatively. The patient was brought to the operating room in extremis and died shortly after repair of the bleeding. Fungal cultures from the aortic suture line were positive for Candida. Two patients had unexplained multiorgan failure after transplantation. An infectious cause was suspected but never proved. Profound neurologic depression developed in both, with eventual coma and brain death. In total, 11 of the first 30 patients (31 heart-lung transplant recipients) died in the hospital (35%). In group 2 there were no deaths, or significant morbidity, from acute graft failure. There were no deaths from bleeding. There were fivein-hospital deaths from 22 to 99
days after heart-lung transplantation. One patient died of acute exsanguination from the aortic suture line 22 days postoperative. The patient was resuscitated, but brain death had occurred during the arrest. Cultures at operation were negative, but the situation again was suggestive of an infection disrupting the suture line. Three other patients died of sepsis. All had pneumonia as the primary site of infection. One died 99 days after transplantation of adenovirus pneumonia. Another patient died 51 days postoperatively with cytomegalovirus (CMV) and Legionellapneumonia. The third was a 2-year-old child who required retransplantation because of rejection and severe adenovirus pneumonia. He died of Candida pneumonitis 57 days after the first heart-lung transplantation and 21 days after the second transplantation. One other patient underwent heart-lung transplantation in group 1, had severe OB, and underwent retransplantation in group 2. Postoperatively he had severe bleeding, renal failure, and CMV penumonia and eventually had a fatal cerebrovascular accident while hypotensive on dialysis. In total, five of the 32 patients (34 heart-lung transplants) died in the hospital (16%), with three recently treated patients still hospitalized. There were 13 late deaths in group 1 (see Table III). Five patients died ofOB. Two other patients with OB required repeat heart-lung transplantation. One (as mentioned earlier in this report) died 37 days after the second operation. Theother required retransplantation 37 months after the initial procedure. This patient eventually died 36 months after the second transplant operation of pneumonia. Two patients died of graft atherosclerosis. The first patient to undergo heart-lung transplantation had an abdominal injury and died of complications of intraabdominal bleeding 63 months after transplantation. At autopsy there were no OB or graft atherosclerosis. There were four late deaths in group 2. One patient died 26 months postoperatively of severe pancreatitis and pneumonia. At autopsy, there was no evidence of coronary graft atherosclerosis or OB. Another patient died of disseminated infection 7 months postoperatively with pneumonia and brain abscess. One patient died of graft atherosclerosis. Finally, one patient died 5 months postoperatively of acute intracerebral bleeding. The overall survival rate in group 2 was significantly higher than in group 1 (p < 0.05 by Gehan and CoxMantel tests). Actuarial survival rates for group I at years I through 6 were 60%, 50%, 43%, 40%, 25%, and 13%, respectively. Survival rates for group 2 at years I through 3 were 73%, 73%, and 65%, respectively (see Fig. 1). Survival of group 2 patients was compared with that of 134 patients who underwent heart transplant at Stanford from March 1986 to April 1989 (see Fig. 2). Survival
Volume 99 Number 1 January 1990
Fig. 1. Comparison of actuarial survival rates in group I (March 1981 to February 1986) and group 2 (March 1986 to April 1989) by Gehan and Cox-Mantel tests (p < 0.05).
Heart-lung transplantation
57
Fig. 2. Comparison of survival rates of group 2 heart-lung transplant recipients and heart transplant recipients treated during the same time period (March 1986 to April 1989) (p= NS).
rates of heart transplant recipients were 78% at 1 year, 70% at 2 years , and 64% at 3 years (p = NS*) None of the patients had significant problems with the tracheal anastomosis or major bronchi either early or late. Two patients early after operation (one in each group) had a pleural air leak with the suggestion of a small tracheal air leak, In both patients the air leak sealed without tracheal dehiscence or mediastinitis. Many patients have small airway disease, 0 B. In group I, there were 19 hospital survivors with OB subsequently developing in 12 of them (63 %). The mean time from heart-lung transplantation to the recognition of OB by pulmonary function tests was 12 months (range 2 to 49 months). Five patients died of OB (two while awaiting retransplantation). Two patients underwent retransplantation : One died 37 days postoperatively and the other 35 months postoperatively. Three other patients were debilitated by their pulmonary dysfunction and died of infection. Two patients are still alive with OB: One has minimal dysfunction and the other is well. In group 2, five patients of the 25 hospital survivors (20 %) had OB. Two patients died of pneumonia. Two patients are alive and are fully functional and rehabilitated, and one has minimal dysfunction. The mean time of onset from transplantation to OB recognition was 8 months (range 3 to 13 months). Six patients in group I are still alive. One has mild limitations on activity from OB (61 months after transplantation) . One other patient has OB but no functional compromise (57 months after heart-lung transplantation). The other four are alive and fully rehabilitated 45 to 78 months after transplantation. Twenty-four patients in group 2 are alive. Three are still in the hospital after the transplant operation. Of the *NS
= Not signi ficant.
21 outpatients, one has pseudotumor cerebri and is mildly limited by neurologic symptoms (37 months after transplantation). One has OB with pulmonary infections and has limited exercise tolerance (32 months after transplantation}. The others are functional and rehabilitated 1 to 35 months after heart-lung transplantation.
Discussion Heart transplantation is an accepted therapy for selected patients with end-stage cardiac disease. Heart-lung transplantation is in a state of evolution ; but for selected patients with end-stage pulmonary disease it can offer long-term rehabilitation. In the 8 years since heart-lung transplantation was begun at Stanford, a great deal has been learned and significant improvements have been made. Patients selected for heart-lung transplantation have all been debilitated and have had a limited life expectancy. Patients with primary pulmonary hypertension and Eisenmenger physiology from congenital heart disease were the most common recipients in both groups. Recently, we have started to perform transplantation in children with these diseases because of the encouraging results obtained in pediatric heart transplants. 16 Four patients with cystic fibrosis were included in group 2. Although the initial results have been satisfactory, the long-term outcome is not yet known. Two patients required retransplantation because of OB. Both had bleeding necessitating early reoperation, and one survived for 3 years, fully rehabilitated, before a fatal pneumonia developed . Currently there are no patients debilitated from OB and awaiting retransplantation, but that would still be a consideration if the need arose. Patients with emphysema resulting from a I-antitrypsin deficiency are
58
The Journal of Thoracic and Cardiovascular Surgery
McCarthy et al.
I
currently considered for heart-lung transplantation (three are awaiting heart-lung transplantation). A major complication has been severe bleeding problems as a result of adhesions formed at previous operations, and our tendency is to avoid patients with extensive previous thoracic or cardiac surgical procedures. However, we still consider patients with previous operations on a case by case basis. Other options for patients with end-stage pulmonary disease include single lung transplantation and double lung transplantation. We currently have three patients with idiopathic pulmonary fibrosis awaiting single lung transplantation. Weare concerned by the significant large airway complications that develop after double lung transplantation.!? and we do not currently offer double lung transplantation for our patients with end-stage pulmonary disease. We have not had large airway problems after heartlung transplantation. Two patients may have had small tracheal leaks, but without major disruption. We have continued therefore to use a continuous suture of 3-0 polypropylene for the tracheal anastomosis, without an omental wrap, as others have reported. I 8 We also have not had late complications of bronchial stenosis. Donor availability is still a major problem. However, with distant procurement now available with PGE I flush, more donors have become available. Therefore more transplants (34) were performed in the most recent 3 years than in the previous 5 years (31). Our results.?'? and those of others,19.20 have indicated the success of this method of preservation. We have had no graft failures with the PGE I flush technique, and we have had prolonged preservation times with up to 3 hours 50 minutes of graft ischemia. OB is still an obstacle to long-term graft function. We believe that OB results from injury to the lung by rejection, or infection, associated with an immune-related disorder," with the healing response to the injury leading to fibrosis and eventual OB. The injury may be related to augmented expression of class II major histocompatibility complex antigens 21,22 and CMV pneumonia.P We24, 25 have found resolution ofOB in some patients after treatment of the rejection episode. Since OB may be reversed by early recognition and treatment of rejection, we have aggressively used bronchoscopy with transbronchiallung biopsy and bronchoalveolar lavage for surveillance of both rejection and infection in our recent patients.P Open lung biopsy has not been used since 1986 to diagnose rejection, and we are encouraged that bronchoscopic surveillance is sensitive and effective. I 5 We know that the comparison of group 1 with group 2 may be somewhat flawed because of the limitations of
a retrospective study. The heart-lung transplantation experience was split at that time because azathioprine was added to augment immunosuppression and distant procurement of heart-lung grafts was initiated. In addition, bronchoscopic surveillance was used much more commonly and as part of a prospective study for the most recent 16 patients.P We think this is a useful time period for assessing our results in terms of survival, although we understand that the division was arbitrary. Although survival was an easily identified result, we purposefully did not compare our results in terms of rejection and infection. In the earliest experience, asynchronous lung rejection was not recognized and therefore not as assiduously evaluated. Aggressive invasive procedures were infrequently used in making the diagnosis in our early experience. Comparisons then between the two groups would not be meaningful. Also, lung infections are more commonly diagnosed by bronchoscopic surveillance because detection is improved. Similarly, OB was not sought, or recognized, early in the program, although this could argue more forceably that OB is less prevalent in the more recent patients. In 8 years much progress has been made in heart-lung transplantation. Asynchronous heart and lung rejection was not recognized when the program was initiated and OB was unknown. Although the survival of our group 2 heart-lung transplantation patients matches our heart transplantation patients during the same time period, the magnitude of the problems facing patients after heartlung transplantation patients is much greater. Infection of the transplanted lung continues to be a major problem and the patients are at high risk of aspiration pneumonia from the upper respiratory tract (e.g., sinuses) because of the diminished cough reflex and impairment of clearance mechanisms in the lower respiratory tracts. We hope that with improved surveillance late complications will diminish and survival will continue to improve. On the basis of our results thus far, this would seem to be a reasonable expectation. We gratefully acknowledge the considerable contributions of Mrs. Janice Keirns and Thomas Flavin, MD, to this manuscript. REFERENCES I. Reitz BA, Burton NA, Jamieson SW, et al. Heart and lung transplantation: Autotransplantation and allotransplantation in primates with extended survival. J THORAC CARDIOVASC SURG 1990;78:569-73. 2. Reitz BA, Bieber CP, Raney AA, et al. Orthotopic heart and combined heart and lung transplantation with cyclosporin A immune suppression. Transplant Proc 1981;13: 393-6. 3. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung trans-
Volume 99 Number 1 January 1990
plantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982;306:557-64. 4. Harjula A, Baldwin JC, Starnes VA, et al, Proper donor selection for heart-lung transplantation. J THoRAc CARDIOVASC SURG 1987;94:874-80. 5. Jamieson SW, Stinson EB, Oyer PE, et al. Operative technique for heart-lung transplantation. J THORAC CARDIOVASC SURG 1984;87:930-5. 6. Starnes VA, Baldwin JC, Harjula A. Combined heart and lung transplantation: the Stanford experience. J Appl Cardiology 1987;2:71-89. 7. Harjula A, Baldwin JC, Shumway DE. Donor deep hypothermia or donor pretreatment with prostaglandin E 1 and single pulmonary artery flush for heart-lung graft preservation: an experimental primate study. Ann Thorac Surg 1988;46:553-5. 8. Baldwin JC, Frist WH, Starkey TD, et al. Distant graft procurement for combined heart and lung transplantation using pulmonary artery flush and simple topical hypothermia for graft preservation. Ann Thorac Surg 1987;43: 670-l 9. Harjula A, Baldwin JC, Stinson EB, et al. Clinical heartlung preservation with prostaglandin E-I. Transplantat Proc 1987;14:4101-2. 10. Reitz BA, Pennock JL, Shumway NE. Simplified operative method· for heart and lung transplantation. J Surg Res 1981;31:1-5. II. Dawkins KD, Jamieson SW, Hunt SA, et al. Long-term results, hemodynamics, and complications after combined heart and lung transplantation. Circulation 1985;71(Pt 2):V919-26. 12. Scott WC, Haverich A, Billingham ME, et al. Lethal rejection of the lung without significa.ntcardiac rejection in primate heart-lung allotransplants. Heart Transplant 1984;37:81-4. 13. McGregor CGA, Baldwin JC, Jamieson SW, et al. Isolated pulmonary rejection after combined heart-lung transplantation. J THoRAc CARDIOVASC SURG 1985;90:623-6. 14. Baldwin JC, Jamieson SW, Oyer PE, et al. Bronchosocpy after Cardiopulmonary transplantation. J THORAC CARDIOVASC SURG 1985;89:1-7. 15. Starnes VA, Theodore J, Oyer PE, et al. Evaluation of heart-lung transplantation recipients with prospective, serial transbronchial biopsiesand pulmonary function studies. J THORAC CARDIOVASC SURG 1989;98:683-90. 16. Starnes VA, Stinson EB, Oyer PE, et al. Cardiac transplantation in children and adolescents. Circulation 1987; 76(Pt 2):V43. 17. Pearson FG. Lung transplantation. Arch Surg 1989; 124:535-8. 18. Griffith BP, Hardesty RL, Trento A, et al. Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 1987;43:6-16. 19. Hakim M, Higenbottam T, English TAH, et al. Distant procurement and preservation of heart-lung homografts. Transplant Proc 1987;14:3535-6. 20. Miyamoto Y, Lajos TZ, Bhayana IN, et al. Beneficial ef-
Heart-lung transplantation 5 9
21.
22.
23.
24.
25.
fects of prostaglandin E 1 on autoperfused heart-lung preservation. J Heart Transplant 1988;7:135-9. Burke CM, Glanville AR, Theodore J, et al. Lung imrnunogenicity, rejection, and obilterative bronchiolitis. Chest 1987;92:547-9. Harjula A, Baldwin JC, Glanville AR, et al. Human leukocyte antigen compatibility in heart-lung transplantation. J Heart Transplant 1987;6:162-6. Burke CM, Glanville AR, Macoviak JA, et al. The spectrum of cytomegalovirus infection following human heart-lung transplantation. J Heart Transplant 1986;5:26772. Allen MD, Burke CM, McGregor CGA, et al. Steroid-responsive bronchiolitis after human heart-lung transplantation. J THORAC CARDIOVASC SURG 1986;92:449-51. Glanville AR, Baldwin JC, Burke CM, et al. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression. Ann Intern Med 1987;107:300-4.
Discussion Dr. BruceA. Reitz (Baltimore, Md.). Dr. McCarthy, I would like to congratulate you and your colleagues on truly spectacular results and significant progress in the field of heart-lung transplantation. I'd like to make several comments and then ask you three questions. In addition to the factors that you have pointed out as improving survival, I believethat your progress is also due to the fact that you have been able to perform a significant number of transplants over the past few years. The programs in England at Harefield in London and Papworth in Cambridge have achieved similar results in a large number of patients and now begin to approach the results after heart transplantation. In this setting the present United Network for Organ Sharing (UNOS) ranking criteria are beginning to work against the heart-lung recipient, because the donors are not offered for heart-lung recipients unless there is no status I heart recipient within 500 miles. This results in fewer donors available for heart-lung recipients. I think the algorithm for assessing UNOS criteria should probably be reexamined given the improved results in heart-lung transplantation. Have you seen any decline in donors with the onset of the UNOS criteria? Has your waiting time for the heart-lung recipients increased? Have any patients on the waiting list been removed from your program because of deterioration of their condition? Dr. McCarthy. It is an honor to have Dr. Reitz discuss this paper because of his pioneering efforts to establish the experimental and clinical heart-lung transplant program at Stanford. We currently have 25 patients awaiting heart-lung transplantation. In the last past we performed 18 heart-lung transplants. Thus the turnover is actually somewhat faster now than it used to be, but the wait still averages about 6 months. Recently three patients died while awaiting a donor, so that the long wait does take its toll. We have not officiallyhad to deactivate any patients because they were becoming too sick for transplantation, but if these three patients had undergone more gradual decline, we would have had to refuse to operate. Donor availability is still a major problem facing heart-lung transplantation.
60
McCarthy et al.
Dr. Cabrol (Paris, France). I would like to congratulate Dr. McCarthy and the Stanford group for their outstanding pioneering work in the field of transplantation, and I wish to thank Dr. Shumway and his group for their continuous support for our team. Among our total experience of 631 transplantations, we performed 46 heart-lung transplantations starting in 1982, soon after the Stanford group began. We also experienced the numerous complications mentioned by Dr. McCarthy, especially excessive bleeding after liberation of dense and diffuse pleural adhesions. To avoid such complications in two patients with previous unilateral thoracotomy and lung resection, we successfully used a procedure described experimentally by Drs. Kawaguchi and Lower, that is, heart and unilateral lung transplantation, which avoided opening the previously treated thoracic side. After en bloc excision of the donor heart and lungs, the unused lung was separated from the heart, and the donor organs
The Journal of Thoracic and Cardiovascular Surgery
were put in their corresponding places in the recipient chest and sutured almost in the usual manner. Do you still consider the existence of dense and diffuse pleural adhesions to be a contraindication for heart-lung transplantation? If not, what technique do you use to avoid excessive bleeding? Dr. McCarthy. Patients who have had a previous operation are still considered for heart-lung transplantation on a case by case basis, depending on the extent of the previous operation. We have not had to use the technique that you described with heart and unilateral lung transplantation, but we have discussed it. We have decided that, if we are faced with a patient with very dense pleural adhesions, we will use that option. We had major complications with bleeding early in the experience but recently have again attempted transplantation in patients who have had a previous operation, and we have not yet had a repeat of our earlier experience.
Improved survival after heart-lung transplantation sixty-two patients underwent 65 heart-lung transplant operations before April 1989. Thirty of these patients (operated on March 1981 to February 1986) were given cyclosporine and prednisone for immunosuppression. These 30 patients (group 1) are compared with the 32 most recent patients (group 2) treated with cyclosporine, prednisone, and azathioprine. Patient characteristics (group 1 versus group 2) were sinillar including age (mean 32 versus 26 years)and indication for operation (51% versus 38%, primary pulmonary hypertension; 46 % versus 45 %, Eisenmenger complex; 3 % versus 17 %, other). The perioperative (in-hospital) mortality rate was 35 % in group 1 versus 16 % in group 2. Obliterative bronchiolitis developed in 12 (63%) of 19 hospital survivors in group 1 from 2 months to 49 months postoperatively (mean 12 months). This complication bas developed in five (20%) of the 25 hospital survivors in group 2 from 3 to 13 months postoperatively (mean 8 months~ Overall, 24 of the 30 patients in group 1 died (infection in eight, obliterative bronchiolitis in five, graft coronary artery disease in two, other causes in nine). Eight of the 32 patients in group 2 died (infection in six, other causes in two), Survival rates for group 1 patients were 60% at 1 year, 50% at 2 years, 43% at 3 years, and 25% at 5 years. Survival rates for group 2 patients were 73% at 1 year, 13% at 2 years, and 65% at 3 years (p < 0.05). When group 2 patients were compared with 134 patients undergoing heart transplantation during the same time period, there was no difference in survival. Routine bron~hoscopic surveillance in the more recent group of patients bas led to the earlier detection of rejection and infection. In combination with decreased perioperative mortality and augmented immunosuppression, this had led to improved survival in our more recent heart-lung transplant recipients. In addition, the earlier recognition of infection and rejection has led to a decrease in severity of obliterative bronchiolitis.
Patrick M. McCarthy, MD (by invitation), Vaughn A. Starnes, MD (by invitation), James Theodore, MD (by invitation), Edward B. Stinson, MD, Philip E. Oyer, MD, and Norman E. Shumway, MD, Stanford, Calif.
h e successful introduction of cyclosporine in heart transplantation and encouraging results with heart-lung transplantation in primates-? preceded the initiation of clinicalheart-lung transplantation at Stanford in 1981.3 Since then many changeshave evolved regarding patient selection, donor organ preservation, postoperative immunosuppression, recognition and treatment of rejectionand infection, and the occurrenceand management oflate sequelae such as obliterativebronchiolitis (OB). Although cardiac transplantation is a more established therapy, From the Departments of Cardiovascular Surgery and Medicine, Stanford University School of Medicine, Stanford, Calif.
much progress has been made with heart-lung transplantation and results are continuingto improve. This report summarizesour entireclinicalexperience withheart-lung transplantation.To emphasizethe progress that has taken place, we divided the experience into two groups on the basis of immunosuppression regimens. The early experience used primarilycyclosporine with prednisone for immunosuppression, and the more recent group (since March 1986) utilizedcyclosporine, prednisone, and azathioprine. The division into twogroups is somewhatarbitrary becauseother changesin management haveevolved in additionto immunosuppression changes,and thesewill also be reviewed.
Read at the Sixty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass., May 8-10,1989.
Patients and methods
Address for reprints: Vaughn A. Starnes, MD, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, cA. 94305.
12/6/16329
54
Sixty-two patients received 65 heart-lung grafts from March 9,1981, until April I, 1989. The clinical characteristics of these patients are summarized in Table I according to two groups. Group 1 comprised patients whose transplant operations were
Volume 99
Heart-lung transplantation
Number 1 January 1990
Table II. In-hospital deaths
Table I. Patient characteristics No. of patients No. H-L Tx Age" (yr) Mean Range Sex, M:F Indications PH
CHD
CF OB Rejection
Group]
Group 2
Tota]
30 31
32 34
62 65
32 22-45 18:12
26 2-44 11:21
29:33
16 14
13 IS
29 29
4 I I
4
I
Postop. day
o I
o o
55
4 II
2 I
H-L Tx, Heart-lung transplants; PH, pulmonary hypertension; CHD, congenital heart disease (Eisenmenger's syndrome); CF, cystic fibrosis; OB, obliterative bronchiolitis; ·Median, 29.3 years.
13 16 20 20 23 33 38 22 37 51
57 99
performed from March 1981 to February 1986 and group 2, from March 1986 to March 1989. Recipients were all disabled by end-stage pulmonary disease and many had severe right heart failure. Patients with renal or primary hepatic disease, diabetes, autoimmune disease, or malignancy were excluded. Twenty-nine patients with congenital heart disease had Eisenmenger physiology. Twenty-seven patients had primary pulmonary hypertension. One patient had pulmonary hypertension resulting from bronchiectasis and another from cardiomyopathy. Four patients with cystic fibrosis recently underwent transplantation. Two patients required repeat transplantation after the development of severe deterioration from OB. One 2-year-old child required repeat transplantation at 1 month because of severe rejection with adenovirus pneumonia. Another patient had failure of the donor heart at implantation. He was supported with an intraaortic balloon pump until a new heart could be transplanted into the graft 24 hours later. The allograft donor selection was particularly stringent." All but one met the following donor criteria: arterial oxygen tension greater than 90 mm Hg on 40% inspired oxygen; peak inspiratory pressure less than 30 em H 20 during respiratory support, with a tidal volume of 12 to 15 ml/kg; and a clear chest film. Donor size was matched to the recipient by body size and thoracic dimensions. The recipient was selected to be the same size or slightly larger than the donor. A Gram stain and tracheal culture were routinely performed on the donor trachea. The first 32 transplants were performed after transport of the donor to Stanford for local procurement of the grafts. For later transplants the organs were preserved with prostaglandin E 1 (PGE I ) as a pulmonary vasodilator, subsequent copious pulmonary artery flush with modified Euro-Collins solution at 4 0 C, and transport with topical cooling."? The most recent 33 transplants were performed in this manner with 21 of the grafts harvested at a distant hospital. The graft implantation operation has been described before.S 6,10 Of particular note, the tracheal anastomosis was performed just above the carina with a continuous suture of 3-0 polypropylene. Omentum was never used to reinforce the suture line. More recent operations have been performed with careful
Cause of death Group]
Pulmonarygraft failure Bleeding complications Bleeding complications Infection (pneumonia) Bleeding complications Bleeding complications Infection (aortic suture line) MOF; brain death MOF; brain death Infection (pneumonia) Infection (mediastinitis) Group 2
Infection? (aortic suture line) MOF; brain death Infection (pneumonia) Infection (pneumonia) Infection (pneumonia)
MOF, Multiple organ failure.
reapproximation of the recipient peritracheal tissue to the donor peritracheal/pericardial tissue around the anastomosis. Two of the recipient hearts (one patient with cystic fibrosis and one with bronchiectasis) were harvested and used for "domino" transplants in heart recipients. In group I, cyclosporine was administered to maintain the radioimmunoassay cyclosporine level between 150 and 250 tig] ml.'! Patients received rabbit antithymocyte globulin for the initial 3 days and azathioprine (1.5 mg/kg/day) for the first 2 weeks. At 2 weeks azathioprine was stopped and 5 mg prednisone twice a day was begun. Maintenance therapy consisted of cyclosporine and prednisone.. For group II patients, cyclosporine was given to maintain a level of 200 to 300 ng/rnl for the first 30 days and 100 to 200 ng/rnl thereafter. Methylprednisolone sodium succinate (SoluMedrol) was given the first 24 hours postoperatively and prednisone was begun on the fourteenth postoperative day (0.4 tug] kg/day initially and then tapered to 0.2 mg/kg/day by discharge). Azathioprine was given as a 4 rug/kg loading dose and then as a maintenance dose of 2 mg/kg/day, The most recent 16 patients received OKTJ (Ortho Diagnostic Systems, Inc., Raritan, N.J.) at 5 mg/kg/day for the first 10 days. Maintenance therapy consisted of cyclosporine, prednisone, and azathioprine. Surveillance for rejection and infection has markedly changed during the clinical program. Initially, endomyocardial biopsy alone was performed weekly while the patient remained in the hospital and as needed for clinical evidence of rejection. I I This practice continues currently, but in addition, after the recognition of asynchronous heart and lung rejection.l- 13 isolated pulmonary rejection has been more carefully evaluated. Although bronchoscopy was used only occasionally in group 1,14 it has become a weekly in-hospital surveillance procedure in the most recent 16 patients'> and as needed for clinical indications of rejection. At bronchoscopy, both transbronchial biopsy and bronchoalveolar lavage were performed. Pulmonary function tests with arterial blood gases were ob-
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56 McCarthy et al.
Table III. Late deaths Postop. month
Causeofdeath Group 1
11 14 15 15
27 35
47 52 53 55 57
63 73
Obliterative bronchiolitis Obliterative bronchiolitis Graft atherosclerosis Infection (pneumonia) Obliterative bronchiolitis Obliterative bronchiolitis Obliterative bronchiolitis Graft atherosclerosis Infection (pneumonia) (Post redo H-L Tx-see group 2) Infection (pneumonia) Intraabdominal bleeding after trauma Infection (pneumonia) re H-L Tx
Group 2 5 7 II
26
Cerebrovascular accident Infection (pneumonia) Graft atherosclerosis Infection (pancreatitis)
tained after extubation, weekly beginning 2 weeks after transplantation,biweekly after 2 months,and at leastevery2 months during the long-termfollow-up. They wereobtainedmoreoften as clinical need dictated. Current clinical follow-up was obtained from the patientsor from their referringphysicians until April I, 1989.
Results In group 1 there was one intraoperative death resulting from acute pulmonary failure with a graft from a donor with borderline blood gas values (see Table II). Four patients died from 1 to 16 days postoperatively of complications related to excessive bleeding. Four other patients died from 11 to 38 days postoperatively of infection. Two of these patients had pneumonia with sepsis. Another patient (who had received a heart transplant for cardiac failure of the heart-lung graft) died of Candida mediastinitis. One other patient bled massively from the aortic suture line 20 days postoperatively. The patient was brought to the operating room in extremis and died shortly after repair of the bleeding. Fungal cultures from the aortic suture line were positive for Candida. Two patients had unexplained multiorgan failure after transplantation. An infectious cause was suspected but never proved. Profound neurologic depression developed in both, with eventual coma and brain death. In total, 11 of the first 30 patients (31 heart-lung transplant recipients) died in the hospital (35%). In group 2 there were no deaths, or significant morbidity, from acute graft failure. There were no deaths from bleeding. There were fivein-hospital deaths from 22 to 99
days after heart-lung transplantation. One patient died of acute exsanguination from the aortic suture line 22 days postoperative. The patient was resuscitated, but brain death had occurred during the arrest. Cultures at operation were negative, but the situation again was suggestive of an infection disrupting the suture line. Three other patients died of sepsis. All had pneumonia as the primary site of infection. One died 99 days after transplantation of adenovirus pneumonia. Another patient died 51 days postoperatively with cytomegalovirus (CMV) and Legionellapneumonia. The third was a 2-year-old child who required retransplantation because of rejection and severe adenovirus pneumonia. He died of Candida pneumonitis 57 days after the first heart-lung transplantation and 21 days after the second transplantation. One other patient underwent heart-lung transplantation in group 1, had severe OB, and underwent retransplantation in group 2. Postoperatively he had severe bleeding, renal failure, and CMV penumonia and eventually had a fatal cerebrovascular accident while hypotensive on dialysis. In total, five of the 32 patients (34 heart-lung transplants) died in the hospital (16%), with three recently treated patients still hospitalized. There were 13 late deaths in group 1 (see Table III). Five patients died ofOB. Two other patients with OB required repeat heart-lung transplantation. One (as mentioned earlier in this report) died 37 days after the second operation. Theother required retransplantation 37 months after the initial procedure. This patient eventually died 36 months after the second transplant operation of pneumonia. Two patients died of graft atherosclerosis. The first patient to undergo heart-lung transplantation had an abdominal injury and died of complications of intraabdominal bleeding 63 months after transplantation. At autopsy there were no OB or graft atherosclerosis. There were four late deaths in group 2. One patient died 26 months postoperatively of severe pancreatitis and pneumonia. At autopsy, there was no evidence of coronary graft atherosclerosis or OB. Another patient died of disseminated infection 7 months postoperatively with pneumonia and brain abscess. One patient died of graft atherosclerosis. Finally, one patient died 5 months postoperatively of acute intracerebral bleeding. The overall survival rate in group 2 was significantly higher than in group 1 (p < 0.05 by Gehan and CoxMantel tests). Actuarial survival rates for group I at years I through 6 were 60%, 50%, 43%, 40%, 25%, and 13%, respectively. Survival rates for group 2 at years I through 3 were 73%, 73%, and 65%, respectively (see Fig. 1). Survival of group 2 patients was compared with that of 134 patients who underwent heart transplant at Stanford from March 1986 to April 1989 (see Fig. 2). Survival
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Fig. 1. Comparison of actuarial survival rates in group I (March 1981 to February 1986) and group 2 (March 1986 to April 1989) by Gehan and Cox-Mantel tests (p < 0.05).
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57
Fig. 2. Comparison of survival rates of group 2 heart-lung transplant recipients and heart transplant recipients treated during the same time period (March 1986 to April 1989) (p= NS).
rates of heart transplant recipients were 78% at 1 year, 70% at 2 years , and 64% at 3 years (p = NS*) None of the patients had significant problems with the tracheal anastomosis or major bronchi either early or late. Two patients early after operation (one in each group) had a pleural air leak with the suggestion of a small tracheal air leak, In both patients the air leak sealed without tracheal dehiscence or mediastinitis. Many patients have small airway disease, 0 B. In group I, there were 19 hospital survivors with OB subsequently developing in 12 of them (63 %). The mean time from heart-lung transplantation to the recognition of OB by pulmonary function tests was 12 months (range 2 to 49 months). Five patients died of OB (two while awaiting retransplantation). Two patients underwent retransplantation : One died 37 days postoperatively and the other 35 months postoperatively. Three other patients were debilitated by their pulmonary dysfunction and died of infection. Two patients are still alive with OB: One has minimal dysfunction and the other is well. In group 2, five patients of the 25 hospital survivors (20 %) had OB. Two patients died of pneumonia. Two patients are alive and are fully functional and rehabilitated, and one has minimal dysfunction. The mean time of onset from transplantation to OB recognition was 8 months (range 3 to 13 months). Six patients in group I are still alive. One has mild limitations on activity from OB (61 months after transplantation) . One other patient has OB but no functional compromise (57 months after heart-lung transplantation). The other four are alive and fully rehabilitated 45 to 78 months after transplantation. Twenty-four patients in group 2 are alive. Three are still in the hospital after the transplant operation. Of the *NS
= Not signi ficant.
21 outpatients, one has pseudotumor cerebri and is mildly limited by neurologic symptoms (37 months after transplantation). One has OB with pulmonary infections and has limited exercise tolerance (32 months after transplantation}. The others are functional and rehabilitated 1 to 35 months after heart-lung transplantation.
Discussion Heart transplantation is an accepted therapy for selected patients with end-stage cardiac disease. Heart-lung transplantation is in a state of evolution ; but for selected patients with end-stage pulmonary disease it can offer long-term rehabilitation. In the 8 years since heart-lung transplantation was begun at Stanford, a great deal has been learned and significant improvements have been made. Patients selected for heart-lung transplantation have all been debilitated and have had a limited life expectancy. Patients with primary pulmonary hypertension and Eisenmenger physiology from congenital heart disease were the most common recipients in both groups. Recently, we have started to perform transplantation in children with these diseases because of the encouraging results obtained in pediatric heart transplants. 16 Four patients with cystic fibrosis were included in group 2. Although the initial results have been satisfactory, the long-term outcome is not yet known. Two patients required retransplantation because of OB. Both had bleeding necessitating early reoperation, and one survived for 3 years, fully rehabilitated, before a fatal pneumonia developed . Currently there are no patients debilitated from OB and awaiting retransplantation, but that would still be a consideration if the need arose. Patients with emphysema resulting from a I-antitrypsin deficiency are
58
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McCarthy et al.
I
currently considered for heart-lung transplantation (three are awaiting heart-lung transplantation). A major complication has been severe bleeding problems as a result of adhesions formed at previous operations, and our tendency is to avoid patients with extensive previous thoracic or cardiac surgical procedures. However, we still consider patients with previous operations on a case by case basis. Other options for patients with end-stage pulmonary disease include single lung transplantation and double lung transplantation. We currently have three patients with idiopathic pulmonary fibrosis awaiting single lung transplantation. Weare concerned by the significant large airway complications that develop after double lung transplantation.!? and we do not currently offer double lung transplantation for our patients with end-stage pulmonary disease. We have not had large airway problems after heartlung transplantation. Two patients may have had small tracheal leaks, but without major disruption. We have continued therefore to use a continuous suture of 3-0 polypropylene for the tracheal anastomosis, without an omental wrap, as others have reported. I 8 We also have not had late complications of bronchial stenosis. Donor availability is still a major problem. However, with distant procurement now available with PGE I flush, more donors have become available. Therefore more transplants (34) were performed in the most recent 3 years than in the previous 5 years (31). Our results.?'? and those of others,19.20 have indicated the success of this method of preservation. We have had no graft failures with the PGE I flush technique, and we have had prolonged preservation times with up to 3 hours 50 minutes of graft ischemia. OB is still an obstacle to long-term graft function. We believe that OB results from injury to the lung by rejection, or infection, associated with an immune-related disorder," with the healing response to the injury leading to fibrosis and eventual OB. The injury may be related to augmented expression of class II major histocompatibility complex antigens 21,22 and CMV pneumonia.P We24, 25 have found resolution ofOB in some patients after treatment of the rejection episode. Since OB may be reversed by early recognition and treatment of rejection, we have aggressively used bronchoscopy with transbronchiallung biopsy and bronchoalveolar lavage for surveillance of both rejection and infection in our recent patients.P Open lung biopsy has not been used since 1986 to diagnose rejection, and we are encouraged that bronchoscopic surveillance is sensitive and effective. I 5 We know that the comparison of group 1 with group 2 may be somewhat flawed because of the limitations of
a retrospective study. The heart-lung transplantation experience was split at that time because azathioprine was added to augment immunosuppression and distant procurement of heart-lung grafts was initiated. In addition, bronchoscopic surveillance was used much more commonly and as part of a prospective study for the most recent 16 patients.P We think this is a useful time period for assessing our results in terms of survival, although we understand that the division was arbitrary. Although survival was an easily identified result, we purposefully did not compare our results in terms of rejection and infection. In the earliest experience, asynchronous lung rejection was not recognized and therefore not as assiduously evaluated. Aggressive invasive procedures were infrequently used in making the diagnosis in our early experience. Comparisons then between the two groups would not be meaningful. Also, lung infections are more commonly diagnosed by bronchoscopic surveillance because detection is improved. Similarly, OB was not sought, or recognized, early in the program, although this could argue more forceably that OB is less prevalent in the more recent patients. In 8 years much progress has been made in heart-lung transplantation. Asynchronous heart and lung rejection was not recognized when the program was initiated and OB was unknown. Although the survival of our group 2 heart-lung transplantation patients matches our heart transplantation patients during the same time period, the magnitude of the problems facing patients after heartlung transplantation patients is much greater. Infection of the transplanted lung continues to be a major problem and the patients are at high risk of aspiration pneumonia from the upper respiratory tract (e.g., sinuses) because of the diminished cough reflex and impairment of clearance mechanisms in the lower respiratory tracts. We hope that with improved surveillance late complications will diminish and survival will continue to improve. On the basis of our results thus far, this would seem to be a reasonable expectation. We gratefully acknowledge the considerable contributions of Mrs. Janice Keirns and Thomas Flavin, MD, to this manuscript. REFERENCES I. Reitz BA, Burton NA, Jamieson SW, et al. Heart and lung transplantation: Autotransplantation and allotransplantation in primates with extended survival. J THORAC CARDIOVASC SURG 1990;78:569-73. 2. Reitz BA, Bieber CP, Raney AA, et al. Orthotopic heart and combined heart and lung transplantation with cyclosporin A immune suppression. Transplant Proc 1981;13: 393-6. 3. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung trans-
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plantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982;306:557-64. 4. Harjula A, Baldwin JC, Starnes VA, et al, Proper donor selection for heart-lung transplantation. J THoRAc CARDIOVASC SURG 1987;94:874-80. 5. Jamieson SW, Stinson EB, Oyer PE, et al. Operative technique for heart-lung transplantation. J THORAC CARDIOVASC SURG 1984;87:930-5. 6. Starnes VA, Baldwin JC, Harjula A. Combined heart and lung transplantation: the Stanford experience. J Appl Cardiology 1987;2:71-89. 7. Harjula A, Baldwin JC, Shumway DE. Donor deep hypothermia or donor pretreatment with prostaglandin E 1 and single pulmonary artery flush for heart-lung graft preservation: an experimental primate study. Ann Thorac Surg 1988;46:553-5. 8. Baldwin JC, Frist WH, Starkey TD, et al. Distant graft procurement for combined heart and lung transplantation using pulmonary artery flush and simple topical hypothermia for graft preservation. Ann Thorac Surg 1987;43: 670-l 9. Harjula A, Baldwin JC, Stinson EB, et al. Clinical heartlung preservation with prostaglandin E-I. Transplantat Proc 1987;14:4101-2. 10. Reitz BA, Pennock JL, Shumway NE. Simplified operative method· for heart and lung transplantation. J Surg Res 1981;31:1-5. II. Dawkins KD, Jamieson SW, Hunt SA, et al. Long-term results, hemodynamics, and complications after combined heart and lung transplantation. Circulation 1985;71(Pt 2):V919-26. 12. Scott WC, Haverich A, Billingham ME, et al. Lethal rejection of the lung without significa.ntcardiac rejection in primate heart-lung allotransplants. Heart Transplant 1984;37:81-4. 13. McGregor CGA, Baldwin JC, Jamieson SW, et al. Isolated pulmonary rejection after combined heart-lung transplantation. J THoRAc CARDIOVASC SURG 1985;90:623-6. 14. Baldwin JC, Jamieson SW, Oyer PE, et al. Bronchosocpy after Cardiopulmonary transplantation. J THORAC CARDIOVASC SURG 1985;89:1-7. 15. Starnes VA, Theodore J, Oyer PE, et al. Evaluation of heart-lung transplantation recipients with prospective, serial transbronchial biopsiesand pulmonary function studies. J THORAC CARDIOVASC SURG 1989;98:683-90. 16. Starnes VA, Stinson EB, Oyer PE, et al. Cardiac transplantation in children and adolescents. Circulation 1987; 76(Pt 2):V43. 17. Pearson FG. Lung transplantation. Arch Surg 1989; 124:535-8. 18. Griffith BP, Hardesty RL, Trento A, et al. Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 1987;43:6-16. 19. Hakim M, Higenbottam T, English TAH, et al. Distant procurement and preservation of heart-lung homografts. Transplant Proc 1987;14:3535-6. 20. Miyamoto Y, Lajos TZ, Bhayana IN, et al. Beneficial ef-
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21.
22.
23.
24.
25.
fects of prostaglandin E 1 on autoperfused heart-lung preservation. J Heart Transplant 1988;7:135-9. Burke CM, Glanville AR, Theodore J, et al. Lung imrnunogenicity, rejection, and obilterative bronchiolitis. Chest 1987;92:547-9. Harjula A, Baldwin JC, Glanville AR, et al. Human leukocyte antigen compatibility in heart-lung transplantation. J Heart Transplant 1987;6:162-6. Burke CM, Glanville AR, Macoviak JA, et al. The spectrum of cytomegalovirus infection following human heart-lung transplantation. J Heart Transplant 1986;5:26772. Allen MD, Burke CM, McGregor CGA, et al. Steroid-responsive bronchiolitis after human heart-lung transplantation. J THORAC CARDIOVASC SURG 1986;92:449-51. Glanville AR, Baldwin JC, Burke CM, et al. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression. Ann Intern Med 1987;107:300-4.
Discussion Dr. BruceA. Reitz (Baltimore, Md.). Dr. McCarthy, I would like to congratulate you and your colleagues on truly spectacular results and significant progress in the field of heart-lung transplantation. I'd like to make several comments and then ask you three questions. In addition to the factors that you have pointed out as improving survival, I believethat your progress is also due to the fact that you have been able to perform a significant number of transplants over the past few years. The programs in England at Harefield in London and Papworth in Cambridge have achieved similar results in a large number of patients and now begin to approach the results after heart transplantation. In this setting the present United Network for Organ Sharing (UNOS) ranking criteria are beginning to work against the heart-lung recipient, because the donors are not offered for heart-lung recipients unless there is no status I heart recipient within 500 miles. This results in fewer donors available for heart-lung recipients. I think the algorithm for assessing UNOS criteria should probably be reexamined given the improved results in heart-lung transplantation. Have you seen any decline in donors with the onset of the UNOS criteria? Has your waiting time for the heart-lung recipients increased? Have any patients on the waiting list been removed from your program because of deterioration of their condition? Dr. McCarthy. It is an honor to have Dr. Reitz discuss this paper because of his pioneering efforts to establish the experimental and clinical heart-lung transplant program at Stanford. We currently have 25 patients awaiting heart-lung transplantation. In the last past we performed 18 heart-lung transplants. Thus the turnover is actually somewhat faster now than it used to be, but the wait still averages about 6 months. Recently three patients died while awaiting a donor, so that the long wait does take its toll. We have not officiallyhad to deactivate any patients because they were becoming too sick for transplantation, but if these three patients had undergone more gradual decline, we would have had to refuse to operate. Donor availability is still a major problem facing heart-lung transplantation.
60
McCarthy et al.
Dr. Cabrol (Paris, France). I would like to congratulate Dr. McCarthy and the Stanford group for their outstanding pioneering work in the field of transplantation, and I wish to thank Dr. Shumway and his group for their continuous support for our team. Among our total experience of 631 transplantations, we performed 46 heart-lung transplantations starting in 1982, soon after the Stanford group began. We also experienced the numerous complications mentioned by Dr. McCarthy, especially excessive bleeding after liberation of dense and diffuse pleural adhesions. To avoid such complications in two patients with previous unilateral thoracotomy and lung resection, we successfully used a procedure described experimentally by Drs. Kawaguchi and Lower, that is, heart and unilateral lung transplantation, which avoided opening the previously treated thoracic side. After en bloc excision of the donor heart and lungs, the unused lung was separated from the heart, and the donor organs
The Journal of Thoracic and Cardiovascular Surgery
were put in their corresponding places in the recipient chest and sutured almost in the usual manner. Do you still consider the existence of dense and diffuse pleural adhesions to be a contraindication for heart-lung transplantation? If not, what technique do you use to avoid excessive bleeding? Dr. McCarthy. Patients who have had a previous operation are still considered for heart-lung transplantation on a case by case basis, depending on the extent of the previous operation. We have not had to use the technique that you described with heart and unilateral lung transplantation, but we have discussed it. We have decided that, if we are faced with a patient with very dense pleural adhesions, we will use that option. We had major complications with bleeding early in the experience but recently have again attempted transplantation in patients who have had a previous operation, and we have not yet had a repeat of our earlier experience.