for Lung Transplantation by xumiaomaio


									The Evolution of Techniques and                                                              Indications
for Lung Transplantation

                                                                                                                JOEL D. COOPER, M.D.

The techniques and indications for lung transplantation have                        From the Division of Cardiothoracic Surgery, and the
evolved significantly in the past 6 years. We initially restricted                        Department of Surgery, Washington University
single-lung transplantation to patients with pulmonary fibrosis                                  School of Medicine, St. Louis, Missouri
and developed the double-lung transplantation procedure for pa-
tients with emphysema or cystic fibrosis. However, with the
double-lung procedure, a 25% mortality rate resulted from isch-
emic complications at the tracheal anastomosis. The technique
was altered to incorporate bilateral bronchial anastomosis, with
a resulting reduction in airway complications. The double-lung              using a technique that has not changed substantially to
transplantation procedure continued to have significant draw-               the present time. Early experience with lung transplan-
backs, including intraoperative and postoperative hemorrhage,               tation documented a deterioration of graft function caus-
and cardiac complications due to prolonged cardiopulmonary                  ing the death of the recipient animal in approximately 7
bypass, ischemic cardiac arrest, and extensive manipulation of              days, a result attributed to rejection. Hardy4 observed that
the heart. These problems recently have been addressed with a
much simplified procedure incorporating a bilateral transverse              the duration of survival in dogs undergoing single-lung
thoracosternotomy, replacement of the right lung without car-               transplantation could be almost doubled by treatment
diopulmonary bypass, and replacement of the left lung with or               with methotrexate, and survival could be further extended
without a short period of partial bypass. This procedure has been           to a mean of 29 days if the animals were treated with
successfully used for emphysema and for cystic fibrosis. The tech-          azathioprine, or azathioprine plus steroids. After extensive
nique of single-lung transplantation also has been simplified and           laboratory investigation, Dr. Hardy performed the first
indications have been expanded to include selected patients with
emphysema and with primary pulmonary hypertension. With sin-                human lung transplantation at the University of Missis-
gle-lung transplantation, each of the lungs from a donor has been           sippi in 1963.5 The donor lung was retrieved postmortem
successfully used for a separate recipient on several occasions,            from a patient who had sustained cardiac arrest, and the
improving the supply of available donor organs.                             recipient survived for 18 days, with death attributed to
                                                                            renal failure and malnutrition.
                                                                               In the next 20 years, approximately 40 attempts at lung
   T n HE ELUCIDATION OF the basis for allograft rejec-                     transplantation were made at many different centers, but
       tion, by Sir Peter Medewar in the 1 940s, laid the                   no long-term clinical success was achieved. The only re-
       foundation for the development of organ trans-                       cipient to leave hospital, and the most notable success in
plantation. The famous Russian physiologist Demikhov                        this period, was a young man who received a lung trans-
successfully performed allografts of individual canine                      plant by Derom and colleagues.6 The initial 8 postoper-
pulmonary lobes in 1947.' In 1950 Metras, in France,                        ative months were spent in hospital, with only a brief
first published the technique of canine pulmonary allo-                     period of survival after discharge. Death was attributed
transplantation.2 He showed remarkable foresight because                    to bronchial complications and infection.
he described a technique of harvesting and anastomosing                        Our initial attempt at lung transplantation, in 1978,
the left bronchial artery to provide systemic blood supply                  resulted in death from bronchial dehiscence in the third
to the airway. In addition he described a left atrial anas-                 postoperative week. A review of world experience at the
tomosis rather than separate pulmonary venous anasto-                       time indicated that major complications relating to the
moses. Hardin and Kittle,3 in 1954, also demonstrated                       bronchial anastomosis had occurred in 16 of the 20 pa-
the technical feasibility of lung transplantation in dogs,                  tients who had survived more than 7 days after lung
                                                                            transplantation. Based on this review, and our initial ex-
                                                                            perience, we embarked on a program in the laboratory to
                                                                            evaluate factors affecting bronchial anastomotic healing
   Presented at the 1 10th Annual Meeting of the American Surgical As-      after lung transplantation. It was postulated that the failure
sociation, Washington, D.C., April 5-8, 1990.                               in bronchial healing might be caused by a combination
   Address reprint requests to Joel D. Cooper, M.D., Division of Car-
diothoracic Surgery, Suite 3108, Queeny Tower, 1 Barnes Hospital Plaza,     of factors, including ischemia of the donor bronchus due
St. Louis, MO 63110.                                                        to transection of the bronchial artery supply, rejection,
   Accepted for publication April 12, 1990.                                 and the effect of immunosuppression, which, at the time,

250                                                        COOPER                                        Ann.   Surg. September 1990

consisted of high-dose prednisone and azathioprine. It was      such as in cystic fibrosis. Furthermore we were concerned
confirmed that the routine use of high-dose steroids in         that unilateral lung replacement for chronic obstructive
the post-transplantation period seriously compromised           lung disease might lead to overexpansion of the native
bronchial healing.7 Cyclosporin could be substituted for        lung and crowding of the transplanted lung, in addition
steroids in the early post-transplantation period with sig-     to a significant ventilation-perfusion mismatch. Such had,
nificant improvement in bronchial healing.8'9                   in fact, been the experience with the 10 cases of single-
   Because clinical application of lung transplantation         lung transplantation for obstructive lung disease reported
generally has not included revascularization of the bron-       between 1963 and 1983."' Cognizant of the success
chial arterial system, we evaluated the use of an omental       achieved with the combined heart-lung transplantation
pedicle wrap around the bronchial anastomosis at the time       in patients with right ventricular failure and pulmonary
of transplantation. This restored bronchial circulation by      hypertension, we began to apply this procedure in patients
means of collateral flow within several days and signifi-       with end-stage respiratory failure due to chronic obstruc-
cantly reduced complications due to bronchial dehiscence        tive or infective disease. In the course of this experience,
and stenosis.' 1 l                                              it soon became evident that such patients generally had
   Based on this laboratory experience, a clinical program      adequate right ventricular function, and inclusion of the
of lung transplantation was begun in 1983. We were en-          heart as part of the transplantation procedure was man-
couraged by reports of successful combined heart-lung           dated primarily for technical reasons not because ofphys-
transplantation by the Stanford group"2 in patients with        iologic necessity. In the laboratory a technique was de-
pulmonary hypertension and chronic right ventricular            veloped for en bloc double-lung transplantation,'6,'7 a
failure. In retrospect lung transplantation often had been      concept initially proposed by Vanderhoeft and co-
applied in desperately ill patients, often in individuals who   workers'8 in 1972. Clinical application of this procedure
depended on a ventilator and who had multisystem fail-          in the first seven patients was reported in 1989.19 In this
ure, for whom transplantation was attempted as a death-         initial series, there was one death and two complications
bed rescue. Initially we chose to use lung transplantation      as a result of airway ischemia, despite use of an omental
in patients with end-stage pulmonary fibrosis. In such pa-      pedicle wrap. Further experience with this procedure
tients the native, remaining lung has markedly diminished       demonstrated a significant incidence of airway compli-
compliance and increased vascular resistance so that ven-       cations.20 In an attempt to reduce airway complications
tilation and blood flow are preferentially directed to the      after the double-lung transplantation procedure, two av-
transplanted lung. Such patients ordinarily do not suffer       enues of investigations were pursued. One method was to
from chronic pulmonary sepsis, and thus the remaining           develop techniques for direct bronchial artery revascu-
lung does not pose an infectious risk. We selected the          larization at the time of the transplant.2' The other was
patients who were continuously dependent on oxygen and          to use bilateral bronchial anastomosis rather than a tra-
had demonstrated progressive deterioration in perfor-           cheal anastomosis because retrograde bronchial artery
mance and pulmonary function during the preceding 12            flow from the lung to the airway becomes more tenuous,
months.                                                         the further the airway anastomosis is from the hilum of
   Patients selected for transplantation were those refrac-     the lung. By using bilateral bronchial anastomoses, the
tory to all forms of medical management, in whom the            incidence of airway complications after double-lung
severity and progression of the disease, and increasing         transplantation has been almost eliminated.22
oxygen requirements, suggested a very limited life expec-          Advantages of the double-lung procedure compared to
tancy. Our initial transplant for pulmonary fibrosis was        the combined heart-lung procedure for end-stage lung
in a 58-year-old man whose transplant was performed in          disease was associated with two distinct advantages: the
November 1983. This recipient recently died of renal fail-      recipient's heart is retained, thus avoiding both the short-
ure 6.5 years after transplantation.                            and long-term complications associated with cardiac
   The experience with lung transplantation for pulmo-          transplantation; and the ability to use lungs from cardiac
nary fibrosis has been gratifying. Ofthe initial 11 patients,   donors increases the supply of transplantable lungs. Re-
nine survived the procedure and were discharged, with           sults obtained with the double-lung transplantation pro-
good performance and no oxygen requirement.'3 An up-            cedure paralleled those achieved with heart-lung trans-
date of the initial 20 patients transplanted for restrictive    plants, with a 1 -year survival rate of 67%. With increasing
lung disease was recently published. 4 In this group there      experience, it was recognized that the double-lung trans-
were four postoperative deaths. Of the remaining 16 pa-         plantation procedure did have limitations: airway isch-
tients, there were 5 late deaths, 3 from chronic rejection,     emia was a significant source of mortality and morbidity;
1 from lymphoma, and 1 from viral infection.                    the transplantation procedure is very complex and difficult
   Initially we thought that unilateral lung transplantation    to teach; extraction of infected lungs, such as in cystic
was contraindicated in the presence of bilateral sepsis,        fibrosis, can be associated with significant intraoperative
Vol. 212 No. 3
                                                           LUNG TRANSPLANTATION                                                     251
and postoperative bleeding problems because the lungs                       porary low-flow cardiopulmonary bypass may be used
are extracted under conditions of total cardiopulmonary                     during replacement of the left lung. This avoids diversion
bypass; postoperative cardiac dysfunction, especially in                    of the entire cardiac output through the newly trans-
recipients with preoperative right ventricular hypertrophy,                 planted right lung, and any associated strain on the right
occurs due to prolonged cardiopulmonary bypass and the                      ventricle that might occur in the face of increased pul-
need for ischemic cardiac arrest during the atrial anas-                    monary vascular resistance. If a partial bypass is used for
tomosis; postoperative exercise studies demonstrated some                   replacement of the second lung, this is easily accomplished
limitation due to a variable degree of cardiac denervation                  by opening the pericardium and inserting a standard aortic
that occurs due to the mediastinal dissection. Postoper-                    cannula and a single left atrial cannula. Bypass flow of 1
ative exercise performance, while very satisfactory, thus                   to 2 L is used to maintain the systolic right pulmonary
showed some of the same limitations that have been re-                      artery pressure at less than 30 mmHg. We have performed
ported in patients undergoing combined heart-lung                           this procedure both with and without the use of cardio-
transplantation.23                                                          pulmonary bypass. Our initial experience recently was
   To address these issues, the technique for bilateral lung                reported.24 Our total experience with this procedure in-
replacement has been completely revised and a more sim-                     cludes seven patients, with no deaths. All patients have
plified and satisfactory approach was developed. This new                   excellent lung function after the procedure and in each
procedure uses the 'old-fashioned,' transverse, bilateral                   case immediate postoperative PA02 on 100% oxygen has
thoracosternotomy through the fourth or fifth interspace                    exceeded 500 mmHg, despite ischemic times of up to 9.5
(Fig. 1). With this approach, superb exposure of both tho-                  hours for the second lung. At 24 hours after operation,
racic cavities from apex to diaphragm is provided. With                     all patients have had satisfactory blood gases on an in-
unilateral lung ventilation, each lung can be completely                    spired oxygen concentration of 30%.
mobilized, taking down adhesions, and isolating the hilar                      Lung function and exercise performance have been ex-
structures. Through an upper midline incision, the omen-                    cellent after this bilateral procedure. Because no medias-
tal pedicle is prepared and split vertically into two pedicles,             tinal dissection occurs, there is no cardiac denervation
one for each side. The right lung is then excised and re-                   with this procedure. Figure 4 demonstrates the preoper-
placed in a fashion similar to that used for single-lung                    ative and postoperative chest x-ray on a 3 1-year-old pa-
transplantation, while the patient is maintained with con-                  tient with cystic fibrosis who underwent this procedure.
tralateral lung ventilation (Fig. 2). After replacement of                  The pre- and postoperative pulmonary function data for
the right lung, the recipient left lung is excised and replaced             this patient are shown in Table 1. We have used this bi-
with the donor left lung (Fig. 3). Each bronchial anasto-                   lateral procedure in two patients in whom exacerbation
mosis is wrapped with a separate omental pedicle. De-                       of chronic respiratory failure required intubation and
pending on right ventricular function, the ischemic time                    ventilation for periods of 1 and 2 weeks, respectively, be-
of the donor lungs, and the stability of the recipient, tem-                fore the transplant procedure. We have been reluctant to
                                                                            extend the transplantation program to individuals with
                                                                            acute respiratory distress syndrome. However the bilateral
                                                                            transplantation procedure would seem well suited for such
                                                                            individuals if a transplant were to be considered.
                                                                               At the same time that improved techniques for bilateral
                                                                            replacement have been developed, the indications for
                                                                            unilateral lung transplantation have significantly ex-
                                                                            panded. Following initial reports from France that uni-
                                                                            lateral lung transplantation had been successfully per-
                                                                            formed in several patients with emphysema,25 we em-
                                                                            barked on a program of single-lung transplantation for
                                                                            patients older than 50 years with end-stage emphysema
                                                                            for whom we thought the initial double-lung transplan-
                                                                            tation procedure was too complex. We have now per-
                                                                            formed 11 such transplants, with no hospital deaths and
                                                                            one late death due to an airway complication. As antici-
                                                                            pated, a significant degree ofventilation to the native lung
                                                                            persists. The results of sequential ventilation and perfusion
FIG. 1. The bilateral lung replacement is performed through a transverse    scans after single-lung transplantation for emphysema are
thoracosternotomy incision using the fourth or fifth interspace. The arms   shown in Figure 5. At six months ventilation to the trans-
are suspended above the face. An upper midline abdominal incision is
used to mobilize the omentum and split it into two pedicles.                planted lung has averaged 61%. This compares with 70%
252                                                      COOPER                                               Ann. Surg. * September 1990


                                                                           FIGS. 2A-C. A technique of right lung excision and re-
                                                                           placement. (A) With the right lung collapsed, the pul-
                                                                           monary artery and pulmonary veins are isolated and di-
                                                                           vided between ligatures or staple lines. The bronchus is
                                                                           transsected and the donor lung positioned in the chest.
                                                                           The bronchial anastomosis is performed first, with a run-
                                                                           ning suture line to the membranous wall. (B) A bronchial
                                                                           anastomosis is completed with interrupted sutures to the
                                                                           cartilaginous portion. The anastomosis is then wrapped
                                                                           with one of the previously prepared omental pedicles. (C)
                                                                           Clamps are placed proximally on the recipient pulmonary
                                                                           artery and an end-to-end pulmonary anastomosis con-
                                                                           structed with running monofilament suture. A left atrial
                                                                           clamp is then placed, an atrial cuff fashioned, and anas-
                                                                           tomosed to the donor atrial cuff with running monofila-
                                                                           ment suture.

ventilation to the transplanted lung for fibrotic lung dis-   ative quantitative lung perfusion scans on patients un-
ease. A report of our overall experience with single-lung     dergoing single-lung transplantation for pulmonary fibro-
transplantation for emphysema is in press.26                  sis and found, in a number of instances, blood flow to the
   Single-lung transplants recently have been used for se-    transplanted lung exceeded 80%, without apparent adverse
lected individuals with primary pulmonary hypertension        effect. To address the second issue, that of right ventricular
as an alternative to combined heart-lung transplantation.     recovery, we conducted a series of experiments in dogs,
Single-lung transplantation for such individuals is pred-     with chronic pulmonary artery banding to produce right
icated on two hypotheses: (1) that the transplanted lung      ventricular failure. Release of the pulmonary artery ob-
must be able to receive virtually the entire cardiac output   struction after a period of 3 to 6 months was associated
immediately, without development of pulmonary edema           with rapid recovery of right ventricular function.27 This
or other pulmonary dysfunction; and (2) that sufficient       laboratory experience paralleled the clinical experience
immediate recovery of right ventricular function must         reported after pulmonary artery thromboendarterectomy
occur to avoid morbidity and mortality in the perioper-       for chronic pulmonary emboli and right ventricular
ative period as a result right ventricular failure. An ad-    failure.28
ditional long-term consideration was the possible adverse        We have performed right lung transplantation in three
physiologic affect of persistent ventilation to the contra-   patients with primary pulmonary hypertension. The initial
lateral lung in the absence of blood flow to that lung. To    patient had systemic pulmonary pressures, despite con-
address the first issue, we obtained immediate postoper-      tinuous prostacycline infusion at the rate of 26 ngs/kg/
Vol. 212 - No. 3                                            LUNG TRANSPLANTATION                                                                253
                                                                                  TABLE 1. Bilateral Lung Transplantation for Cystic Fibrosis
                                                                                  Measurement            Preoperative           Postoperative
                                                                                     V.C.                   1.69                   3.90
                                                                                     FEV,                   0.52                   3.82
                                                                                     DLCO                  12.5                   22.8
                                                                                     R.V.                   4.26                   2.43
                                                                                     P02                   61.0 (3L)              72.0 (RA)
                                                                                Pre- and postoperative (10 weeks) pulmonary function studies on a
                                                                             31-year-old man undergoing a bilateral lung replacement for cystic fi-

                                                                             (Table 2). For reasons not clearly understood, long-term
                                                                             exercise tolerance in these patients has been excellent,
                                                                             with no apparent dyspnea or restriction of exercise ca-
                                                                             pacity, despite persistent, significant ventilation to the na-
                                                                             tive lung in the absence of perfusion to that lung.
FIG. 3. Technique of left lung replacement. After replacement of the            Successful single-lung transplantation also has been re-
right lung, the left lung is excised and replaced in a similar fashion. In   ported successfully in individuals with primary pulmonary
this drawing the bronchial anastomosis has been complete and the pul-        hypertension secondary to cardiac defects, such as patent
monary anastomosis is being accomplished. Division ofthe ligamentum
arteriosum allows the pulmonary artery clamp to be placed as proximal        ductus arteriosus and atrial septal defect.29'30
as possible on the left pulmonary artery.                                       A significant advantage of the single-lung transplan-
                                                                             tation procedure is the ability to use each of the donor
                                                                             lungs for separate recipients, a procedure we call 'twin-
minute. All three patients had depressed right ventricular                   ning.' We have used it for two simultaneous transplants
function, patient 3 having a preoperative right ventricular                  in our own institution, as well as for sharing of the donor
ejection fraction of less than 10%. The right ventricular                    lungs with other institutions.
ejection fraction in this patient, immediately following                        Many problems still must be solved in the field of lung
right lung transplantation, improved to 40%. A quanti-                       transplantation. Chief among them, perhaps, is the very
tative lung perfusion scan obtained within hours of the                      limited availability of suitable organs for transplantation.
transplantation procedure showed perfusion to the trans-                     This is caused not only by the general paucity of donors
planted lung in excess of 90% in all three patients. Re-                     but also by the rapid deterioration of lungs after brain
covery has been excellent, with all patients having normal                   death. This is further complicated by often conflicting
cardiac function on postoperative cardiac catheterization                    views on donor management by the various organ teams.

FIGS. 4A and B.           (A) Before
and (B) after chest x-ray        on

a   3 1 -year-old   man   with
fibrosis. Bilateral lung re-
placement was performed
using the transverse thora-
costernotomy approach.
254                                                                       COOPER                                                 Ann. Surg. * September 1990

            SINGLE LUNG TRAP ISPLANT                                            of rejection in the early postoperative period remains
                FOR EMPHYSEEMA                                                  largely empiric, based on clinical findings, including tem-
                  % Ventilation and Pekrfusion                                  perature, diminishing PAO2, development of pulmonary
                     to Transplanted lLung                                      infiltrates, and/or changes in quantitative lung perfusion
                                                                                scans. The routine use of transbronchial lung biopsies for
                                                                                the diagnosis of chronic pulmonary rejection has been
                                                                                valuable, especially in distinguishing between rejection
                                                                                and viral infection, such as cytomegalovirus (CMV) in-
                                                                                fection. Chronic rejection in the form of bronchiolitis ob-
                                                                                literans has occurred frequently after combined heart-
                                                                                lung transplantation. This was not recognized initially af-
Pre Op            Post Op         1 month         3 months        6 months      ter single-   or   bilateral-lung transplantation procedures, but
                                   Time                                         with increasing experience several cases have been ob-
    *    Ventilation                  11 Perfusio Wn
                                                                                served in such recipients. Whether the incidence of bron-
FIG. 5. Quantitative ventilation and perfusion sc :ans in patients undergoing   chiolitis obliterans will approach that observed following
single-lung replacement for emphysema. In j
worst function is usually replaced, hence the p reoperative values are less     the combined heart-lung transplant procedure remains
than 50% for the lung that is subsequently relplaced. Ventilation to the        to be seen.
transplanted lung averages 60% at 6 months. T his compares with a mean             Techniques and indications for single and bilateral lung
of 70% in patients undergoing single-lung reDplacement for restrictive          transplantation have evolved significantly in            the

lung disease.
                                                                                eral years such that successful transplantation can now
                                                                                be achieved routinely, with success rates approaching
Retrieval of all satisfactory organs friom a donor requires                     those seen with other organ transplants. Using current
close cooperation and judicious man agement in terms of                         techniques we have performed 24 single- or bilateral-lung
fluid administration, use of inotropic support, and overall                     transplants in the past 12 months, with no hospital deaths.
donor management. Nonetheless, iin a number of in-                              There have been two late deaths, one due to CMV infec-
stances, lungs, heart, liver, kidneys, a .nd pancreas all have                  tion at 6 months in a patient transplanted for complica-
been successfully transplanted from one donor.                                  tions of chemotherapy for Hodgkin's disease, and the
   Using current preservation techniq ues, which primarily                      other due to airway complications 2 months after a single-
consist of flushing of the lungs with cold electrolyte so-                      lung transplant. As with other organ transplants, the major
lution, an ischemic time of 6 hours is, well tolerated. With                    problems to be resolved include availability of suitable
the bilateral lung replacement tech nique, in which the                         donor organs, improved immunosuppressive regimens,
ischemic time for the second lung is longer than the first,                     and the ability to promptly diagnose and effectively treat
ischemic times of 7.5 to 9.5 hours                for   the   second   lung             rejection.

have been well tolerated. We have rezcently reported suc-
cessful 12-hour lung preservation in za canine model using                                                Acknowledgments
a low potassium-containing electrollyte solution.3' Cur-
                                                                                  The author thanks research fellows and colleagues at Washington
rently, using a baboon model of bila[teral lung transplan-                      University School of Medicine and at the University ofToronto, including
tation, ischemic times of 12 and 14I hours for the right                        Drs. Larry Kaiser, Michael Pasque, Elbert Trulock, James Cox, Nicholas
and left lungs, respectively, have bee n well tolerated with                    Kouchoukas, F. G. Pearson, Robert Ginsberg, Alec Patterson, Melvyn
excellent postoperative lung functioin.                                         Goldberg, T. R. J. Todd, W. DeMajo, and A. Triantifillou for their many
                                                                                important contributions to this work.
   The diagnosis and treatment ofboith acute and chronic
rejection remains a troublesome pro)blem. The diagnosis
         TABLE 2. Single-lung Transplant for P'rimary Pulmonary                  1. Demikhov VP. Experimental transplantation of vital organs. New
           Hypertension: Cardiac Catheterizatlion Data, n = 3                          York: Consultants Bureau Enterprises, 1962.
                                                                                 2. Metras H. Note preliminaire sur la greffe totale du poumon chez le
     Measurement                Preoperative             Postoperative                 chien. CR Acad Sci (Paris) 1950; 231:1176-1178.
                                                                                 3. Hardin CA, Kittle CF. Experiences with transplantation of the lung.
        PA (mean)                    53                        15                      Science 1954; 119:97-98.
        PVR                        1130                       198                4. Hardy JD, Eraslan S, Dalton ML. Autotransplantation and ho-
        RA pressure                   5                         0                      motransplantation of the lung: further studies. J Thorac Car-
        C.O. (liters)                 3.4                       5.7                    diovasc Surg 1963; 46:606-615.
                                                                                 5. Hardy JD, Webb WR, Dalton ML, et al. Lung homotransplantation
   Pre- and postoperative cardiac catheterization data in three patients               in man. JAMA 1963; 186:1065-1074.
undergoing right lung transplantation for primary pulmonary hyperten-            6. Derom F, Barbier F, Ringoir S, et al. Ten month survival after lung
sion. All patients showed normal cardiac function when restudied 3 to                  homotransplantation in man. J Thorac Cardiovasc Surg 1971;
6 weeks after the transplant.                                                          61:835-846.
Vol. 212 No. 3                                                LUNG TRANSPLANTATION                                                                      255
  7. Lima 0, Cooper JD, Peters WJ, et al. Effects of methylprednisolone                  for advanced chronic obstructive lung disease. Am Rev Respir
        and azathioprine on bronchial healing following lung transplan-                  Dis 1989; 139:303-307.
        tation. J Thorac Cardiovasc Surg 1981: 82:211-215.                      20.   Patterson GA, Todd TR, Cooper JD, et al. Airway complications
  8. Goldberg M, Lima 0, Morgan E, et al. A comparison between cy-                       after double lung transplantation. J Thorac Cardiovasc Surg 1990;
        closporin A and methylprednisolone plus azathioprine on bron-                    99:14-21.
        chial healing following canine lung autotransplantation. J Thorac       21.   Schreinemakers HJ, Weder W, Miyoshi S, et al. Direct revascular-
        Cardiovasc Surg 1983; 85:821-826.                                                ization of bronchial arteries for lung transplantation: an anatom-
  9. Saunders NR, Egan TM, Chamberlain D, et al. cyclosporine and                        ical study. Ann Thorac Surg 1990; 49:44-53.
        bronchial healing in canine lung transplantation. J Thorac Car-         22.   Noirclerc M, Metras D, Vaillant A, et al. Technique chirurgicle de
        diovasc Surg 1984: 88:993-999.                                                   la transplantation bi-pulmonaire. Lyon Chirurgical 1989; 85:247-
10. Dubois P, Choiniere L, Cooper JD. Bronchial omentopexy in canine                     251.
        lung allotransplantation. Ann Thorac Surg 1984; 38:211-214.             23.   Sciurba FC, Owens GR, Sanders MH, et al. Evidence of an altered
11. Lima 0, Goldberg M, Peters WJ, et al. Bronchial omentopexy in                        pattern of breathing during exercise in recipients of heart-lung
        canine lung transplantation. J Thorac Cardiovasc Surg 1982: 83:                  transplant. N Engl J Med 1988; 319:1186-1192.
        418-421.                                                                24.   Pasque MK, Cooper JD, Kaiser LR, et al. An improved technique
12. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation:                   for bilateral lung transplantation: rationale and initial clinical
        successful therapy for patients with pulmonary vascular disease.                 experience. Ann Thorac Surg 1990; 49:785-791.
        N Engl J Med 1982; 306:557-564.                                         25.   Mal H, Andreassin B, Pamela F., et al. Unilateral lung transplantation
13. The Toronto Lung Transplant Group. Experience with single lung                       in end stage pulmonary emphysema. Am Rev Respir Dis 1989;
        transplantation for pulmonary fibrosis. JAMA 1988; 259:2258-                     140:797-802.
        2262.                                                                   26.   Cooper JD, Kaiser LR, Trulock EP, et al. The evolution of lung
14. Grossman RF, Frost A, Zamel N, et al. Results of single-lung trans-                  transplantation for emphysema. JTCVS. Accepted for publica-
        plantation for bilateral pulmonary fibrosis. N Eng J Med 1990;                   tion.
        322:727-733.                                                            27.   Hsieh CM, Mishkel G, Rakowski H, et al. Production and revers-
15. Stevens PM, Johnson PC, Bell RL, et al. Regional ventilation and                     ibility of right ventricular hypertrophy and right heart failure in
        perfusion after lung transplantation in patients with emphysema.                 dogs. Submitted for publication.
        N Engl J Med 1970; 282:245-249.                                         28.   Daily PO, Dembitsky WP, Peterson KL, et al. Modifications of
16. Dark JH, Patterson Ga, Al-Jilaihawi AN, et al. Experimental en                       techniques and early results of pulmonary thromboendarterec-
        bloc double-lung transplantation. Ann Thorac Surg 1986; 42:                      tomy for chronic pulmonary embolism. J Thorac Cardiovasc
        394-398.                                                                         Surg 1987; 93:221-233.
17. Patterson GA, Cooper JD, Dark JH, et al. Experimental and clinical          29.   Fremes FE, Patterson GA, Williams WG, et al. Single lung transplant
        double lung transplantation. J Thorac Cardiovasc Surg 1988: 95:                  and closure of patent ductus arteriosus for Eisenmenger's syn-
        70-74.                                                                           drome. J Thorac Cardiovasc Surg (In press).
18. Vanderhoeft P, Dubois A, Lauvau N, et al. Block allotransplantation         30.   Starnes V. Oral personal communication, March 1990.
        of both lungs with pulmonary trunk and left atrium in dogs.             31.   Keshavjee SH, Yamazaki F, Cardoso, et al. A method for safe 12
        Thorax 1972; 27:415-419.                                                         hour pulmonary preservation. J Thorac Cardiovasc Surg 1989;
19. Cooper JD, Patterson GA, Grossman R, et al. Double-lung transplant                   98:529-534.

                               DISCUSSION                                         At the other end of the immunologic spectrum we reasoned that heart
                                                                               and liver, derived from mesoderm and entoderm, would prove to be
   DR. FRANK J. VEITH (New York, New York): I think Dr. Cooper is              least antigenic, with the kidney somewhere in between.
to be congratulated for bringing this field to clinical fruition. As many
                                                                                  Now that you have obtained a series of long-term lung allografts, are
of you know, we worked tirelessly in it for many years and presented a
                                                                               your rejection episodes less or more frequent and intense than for your
paper on single lung transplantation for emphysema with a clinically
                                                                               liver and renal allografts?
successful patient to this organization in 1973 (Ann Surg 178:463, 1973).
   I think still the major problem in this field and the item that prompted
us to withdraw from the field is the difficulty in procuring donor lungs.         DR. JOHN R. BENFIELD (Sacramento, California): One of the problems
Many donors that are suitable for other organ transplantation still have       in the early days of lung transplantation was the differentiation of rejection
diseased, infected lungs, and this is going to be the limiting factor in the   from infection in the postoperative period (Benfield JR. Transplantation
clinical application of lung transplantation. Accordingly, we have de-         of the Lung. In Kirkpatrick CH, Reynolds HY, eds. Immunologic and
veloped a technique for procuring both lungs from the same donor after         Infectious Reactions in the Lung. New York: Marcel Dekker, 1976, pp
completion of a heart donation (Surg Gynecol Obstet, 166:363, 1988).           485-518). I think that it would be very helpful to us to hear how you
Despite this, the donor problem remains.                                       accomplish this differentiation at present.
   DR. JOSEPH E. MURRAY (Boston, Massachusetts): Some 40 years ago
when we started working on human and experimental renal transplan-                DR. HERBERT B. HECHTMAN (Boston, Massachusetts): I think you
tation at the Peter Bent Brigham Hospital and Harvard Medical School           have the stick-to-itiveness that is really needed to not only do it, but to
we noted that renal allografts in humans were not rejected as rapidly as
                                                                               sell it to the audience.
skin allografts. It seemed surprising that a large vascularized whole-organ       Perhaps you can tell us what your current preservation techniques are
graft would elicit less immunologic response than a small postage-stamp-       and what the problems of reperfusion pulmonary edema are in your
sized skin graft.                                                              ischemic lungs.
   Accordingly we tried to identify on an a priori basis a hierachy of
organ antigenicity. We theorized that skin and lung would be the two
most difficult organs to allotransplant because each had an epithelial            DR. JOEL D. COOPER (Closing discussion): First, what a thrill to be
surface exposed to the external environment and accordingly over the           sandwiched in between comments by Drs. Starzl and Hardy, and it is
evolutionary ages had built up the greatest natural immunity to foreign        exciting to have Dr. Hardy in the audience. His first pioneering attempt
proteins. To support this theory we noted that the two most common             followed many years of important laboratory investigation. We are all
allergic conditions afflicting humans, that is, asthma and dermatitis, in-     indebted to him as we are to Dr. Veith, who for many years in the dark
volve lung and skin.                                                           ages kept the candle of hope flickering in this area. Had it not been for

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