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ANNALS OF SURGERYVol. 223. No. 5, 576-584@ 1996 Lippincott-Raven Publishers

Peter Van Trigt, M.O., R. Duane Davis, M.O., Gail S. Shaeffer, R.N., J. William Gaynor, M.O.,Kevin P. Landolfo, M.O., Michael B. Higginbotham, M.O., VictorTapson, M.O.,and Ross tv1. Ungerleider, M.O.

From the Divisions o( Cardiothoracic Surgery, Cardiology, and Pulmonary Medicine, DukeUniversity Medical Center, Durham, North Carolina

ObjectiveHeart and lung transplantation has gained acceptance as therapy for end-stage cardiac andpulmonaryfailure. The early and intermediate survival benefits of one center's 10-year experiencewith 177 patients undergoing thoracic transplantation were examined.

Summary Background DataAs experience in cardiac and pulmonary transplantalion has increased, improvements in patientselection, organ preservation, preoperative support, and perioperative Gafe have significantlyreduced the early threals lo patienl survival. Graft dysfunclion due to chronic rejeclion appears tobe the main risk for longer-term survival, and data compiled by1he United Network for OrganSharing (UNOS) indicate a 70% 5-year survival for heart transplants and a 50% 5-year survival for

lung transplant recipients.

MethodsThe medical records of 120 heart recipients, 52 lung transplant recipients., and 5 heart-lungrecipients were reviewed. Cumulative suNival estimates were made using Kaplan-Meier analysis.The etiologies of operative and long-term mortality in each transplant population were jdentified. Acomparison of long-term suNival after heart transplantation versus coronary revascularization in agroup of patients with ischemic cardiomyopathy was performed.

ResultsOperative mortality in both the cardiac and pulmonary transplant recipients was 8%. From 1990 to1995. 70 consecutive adult cardiac transplant procedures were performed~o~t §;n °Berativecmortality. Three of five patients survived heart-lung transplantation. The extended actuarialsUrviVarrate ~2.1-~~~80-.!o fQ[ th~r2!ac tran_sg.!ant re~ipie1lts. The 2-year actuarial survivalrate for the lung transplant recipients was 88%. Graft dysfunction was the most common cause ofoperative mortality in the heart transplant group whereas infection was responsible for most of theoperative mortality after lung transplantation.

ConclusionsCardiac and pulmonary transplantation can be applied to morbidly ill patients with excellentoperative and intermediate-term survival.

576

577Vol. 223. No. 5 Survival Benefits of Heart and Lung Transplantation

Since the clínica! introduction of heart, lung, andheart-lung transplantation in the 1960s, thoracic trans-plantation has become an established forro oftherapy forpatients with end-stage heart and lung disease. CurrentUnited Network for Organ Sharing (UNOS) statistics in-dicate that the annual number ofthoracic organ replace-ments is approximately 2000 hearts per year, 800 lungsper year, and 60 heart-lungs per year. The transplantsurvival data compiled by UNOS indicate a 70% 5-yearsurvival rate in heart transplant recipients and a 50% 5-year survival rate in lung transplant recipients. Thegreatest impediment to increased application of trans-plantation for end-stage heart and lung disease has beena limitation of donors. This has resulted in large waitinglists (3000 hearts, 1600 lungs) and has led to the develop-ment of alternative and currently experimental interven-tions that might enhance survival in these end-stage pa-tients. These new technologies include laser createdtransmyocardial vascular channels, cardiomyoplasty,and permanent implantation ofleft ventricular assist de-vices for cardiac patients,1 and volume reduction lungsurgery for patients with advanced chronic obstructivepulmonary dise~se. The benefits of such new therapiesfor end-stage heart and lung disease are yet to be definedand compared with the realities ofheart and lung trans-plantation. The purpose of this report is to review onecenter's experience in thoracic transplantation in thecurrent cyclosporine era and to document the survivalbenefits that can be achieved with heart, lung, and heart-lung transplantation.

III to IV symptoms of congestive beart failure associatedwitb an ejection fractíon of less iban 20%.2 Tbese pa-tients were considered only if pulmonary vascular resis-tance measured less iban 7 wood units beca use of tbebigb risk of donor right ventricular failure in recipientswitb pulmonary bypertension.3 Otber criteria includedabsence of irreversible renal or bepatic dysfunction, ab-sence of infection, and demonstrated compliance witbmedicaltberapy.

Tbe indications for lung transplantation included tbepresence of end-stage lung disease witb a life expectancyless iban 18 montbs. Generally, tbe forced expiratoryvolume in 1 second (FEV .) was less iban 20% predictedfor patients witb chronic obstructive pulmonary diseaseand less iban 30% predicted for patients with cystic fi-brosis.4 Pulmonary transplantation was applied to pa-tients witb primary and secondary pulmonary hyperten~sion wben the mean pulmonary artery pressure wasgreater iban 85 mmHg and the patient bad class III orgreater symptoms of respiratory insufficiency. Singie-lung transplantation was applied to patients youngeriban 65 years of age witbout infectious lung disease,wbereas bilateral sequentiallung transplantation was ap-plied to patients younger iban 55 years of age, tbose witbinfectious lung disease (cystic fibrosis), and patients witbeitber primary or secondary pulmonary hypertensionwbo had normal left ventricular function. Patients ac-cepted for lung transplantation bad no other significantsystemic disease, were nonsmokers, and had demon-strated medical compliance. Heart-Iung transplantationwas reserved for patients with Eisengmenger's syndromewitb biventricu/ar failure or complex congenital heartdisease not correctable witb conventional cardiac sur-gery.

MATERIALS AND METHODS

The records of 177 patients receiving thoracic organreplacement at Duke University Medical Center be-tween April 1985 and April 1995 were reviewed. Thecardiac transplant program was initiated in 1985, andthe long transplant and heart-Iung transplant programsbegan in 1992 (Fig. 1). AII transplant operations per-formed since 1987 were performed by the same group oftransplant surgeons, and an attending surgeon partici-pated in all donar procurement procedures.

Operative Techniques

The operative techniques of heart, lung, and heart-lung implantation as well as donor harvest and preserva-tion were standardized according to institutional proto-cols. All hearts were preserved with a routine crystalloidhyperkalemic cardioplegia, and lungs were flushed witha modified Euro-Collins solution preceded by 500 JLg ofprostaglandin El- Aprotinin was used routinely for hearttransplant procedures performed through a prior ster-notomy and alllung transplants requiring cardiopulmo-nary bypass. Inhaled nitric oxide has been used in thepast 12 months for heart transplant recipients with sig-nificant right ventricular dysfunction and almost rou-tinely after single or bilateral lung transpl~ntation. Astandard cyclosporine-based triple drug immunosup-pressive regimen was used for all transplant recipients.5

Patient Selection CritE~ria for

Transplantation

The general indications followed for cardiac trans-plantation included age younger than 65 years with class

Presented at the 107th Annual Session ofthe Southern Surgical Asso-ciation, December 3-6, 1995, Hot Springs, Virginia.

Address reprint requests to Peter Van Trigt, M.O., Box 3235, DukeUniversity Medica! Center, Durham, NC 27710.

Accepted for publication January 4, 1996.

578 Van Trigt and Others Ann. Surg .May 1996

Figure 1. Thoracic organ transplantvolume per year at Duke UniversityMedical Center.

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995

Patient Characteri~;tics: HeartTransplantation

The cardiac transplant group included 120 patients,with 86 males and 34 females (Table 1). The mean age atthe time of transplantation was 45.6 :t 3.6 years, withan age range of 3 weeks to 64 years. The most commondiagnosis ofthe recipient was ischemic cardiomyopathy(n = 60), with idiopathic cardiomyopathy representingthe other majar recipient diagnosis (n = 51). The remain-der ofthe recipient diagnoses are listed in Table 2.

The mean pretransplant ejection fraction was 15% :t5% with a range of 4% to 21 %. Of the 120 heart recipi-ents, 16 experienced an episode of cardiac arrest requir-ing cardiopulmonary resuscitation (CPR) preopera-tively. Tbe severity ofillness ofthis patient population isreflected by the fact that 104 patients were UNOS Status1 before transplantation (requiring mechanical or in 0-tropic drug support in intensive care) and the remainderwere UNOS Status 2. Approximately one third ofthe pa-tients had undergone previous sternotomy for coronaryartery bypass grafting or other cardiac procedures. A me-

chanical bridge to transplantation was used in 31 pa-tients when inotropic support was inadequate (Table 3).An intra-aortic balloon pump was used for circulatorysupport in 25 patients, predominantly those with isch-emic cardiomyopathy, for periods of up to 160 days.When an intra-aortic balloon pump was inadequate topro vide hemodynamic stability, the HeartMate left ven-tricular assist device (Thermo Cardiosystems, Inc., Wo-bum, MA) was used to support 4 patients (range, 20-105days) who were all successfulIy transplanted. One earlypatient was supported with the Anstadt cup ventricularactuator (Advanced Resuscitation Innovations, Inc.,Tipp City, OH) for3 days before being successfully trans-planted.6 The average pretransplant length of stay forStatus 1 patients was 54 :t 7 days.

Cardiac donar selection criteria included age youngerthan 60 years with a negative history of cardiac disease.A two-dimensional echocardiogram was performed onvirtualIy alI potential donors, and significant walI motionabnormalities usualIy would disqualify a heart for trans-plantation.7 Acceptable donar inotropic support was de-fined as 15 ¡.tg/kg per minute (or less) ofdopamine andcoronary arteriograms were performed, when possible,on donors o.1der than 50 years of age. Significant coro-nary lesions (~ 50% stenosis) would preclude use of adonar heart.8

Table 1. THORACIC TRANSPLANTRECIPIENTS: CL.lNICAL CHARACTERISTICS

No. ofPatients

Age(yr) (range)Organ MalejFemale

Heart

LungHeart-lung

12052'

5

86/3429/333/2

46.5 (3 wk-64 yr)46.5 (20-66 yr)33.8 (17-42 yr)

Patient Characteristics: LungTransplantation

Between 1992 and Apri11995, 52 patients underwentlung transplantation. The group included 29 men and 23women, with a mean age of 46.5 :t 3.5 years (range, 20-66 years). Single-lung transplantation was performed in

.Single, 30 patients; bilateral, 22 patients.

579Survival Benefits of Heart and Lung TransplantationVol. 223. No. 5

Table 2. HEART TRANSPLANT RECIPIENTDIAGNO!;IS (N = 120)

mean time on the waiting list for lung transplant recipi-ents was 10 :t: 2 months.

Donor lungs were evaluated with a chest x-ray, arterialblood gas on 100% fraction of inspired oxygen (FiO2)and flexible bronchoscopy. In general, donors were ac-ceptable if they were younger iban 55 years of age withless iban a 20-pack/year history of smoking. A chest x-ray clear of significant airspace disease with a partialpressure of oxygen (PO2) greater iban 300 mmHg on100% FiO2 was required. Bronchoscopy was used to doc-ument absence ofpersistent purulent secretions withoutevidence of aspiration characterized by significantedema and erythema of the airways. The donor lungswere flushed with 4 L ofmodified Euro-Collins solutionpreceded by infusion of 500 ,ug of prostaglandin El be-fore the aorta was cross-clamped.11

Diagnosis No.

Ischemic cardiomyopathy

Idiopathic cardiomyopathy

CongenitalRestrictive

PostpartumVira! myocarditis

60514221

Patient Characteristics: Heart-LungTransplantation

Our approach to heart-Iung transplantation is to per-forro the procedure only when lung transplantation withrepair of a cardiac lesion (ventricular septal defect, atrialseptal defect), which has resulted in Eisenmenger's syn-drome, is not possible.12 Patients with primary pulmo-nary hypertension, even those with severe right ventric-ular dysfunction, will do well after bilaterallung trans-plantation if the left ventricle is normal. The rightventricle shows significant and immediate improvementwith normalization of afterload after lung replacement.We prefer to use the transverse "clam shell" incision viabilateral anterior thoracotomy to perform heart-Iung re-placement because ofimproved exposure ofhilar struc-tures and the posterior mediastinum, which can be thesource of significant bleeding from systemic collateralvessels. The five patients undergoing heart-Iung trans-

30 patients; 22 patients received bilateral sequentiallungtransplants. The most common recipient diagnosis waschronic obstructive pulmonary disease (24 patients),with cystic fibrosis representing the next largest group(10 patients), as summarized in Table 4. Bilaterallungtransplantation was performed on all patients with cysticfibrosis, primary pulmonary hypertension, and Eisen-menger's syndrome with intact left ventricular function.9Bilateral sequentiallung transplants also were performedon selected young patients (less iban 50 years) with ob-structive or restrictive disease to provide them with thepotential for a greater long-term survival, anticipatingthat the risk for chronic graft dysfunction secondary tobronchiolitis obliterans would be less severe.IO

Ofthe 52 patients undergoing lung transplantation, 13patients were critically ill requiring pretransplant hospi-talization. Ventilator support was req uired for five pa-tients for a period of8 days to 4 months. Ofthe patientsrequiring pretransplant mechanical ventilation, four offive survived transplantation; one patient with cystic fi-brosis died of Pseudomonas bacteremia shortly aftertransplantation. A patient on the waiting list who deteri-orates to the point ofrequiring mechanical ventilation iskept active for transplantation as long as the patient cancontinue to undergo physical therapy. Tracheostomywas used to allow ventilated ambulation in two ofthe fivepatients on pretransplant mechanical ventilation. Eightother patients were hospitalized, clase to requiring intu-batían, on up to 12 L per minute of oxygen therapy. The

Table 4. LUNG TRANSPLANT RECIPIENTDIAGNOSIS

Diagnosis No.

241054421

Table 3. PRE-HEART TRANSPLANTMECHANICAL SUPPORT

No.Mechanical Support

IABPLVADECMO

25 (7-160 days)5 (3-105 days)1 (7 days)

COPOCystic fibrosis

Primary pulmonary hypertensionPulmonary fibrosis

a1"Antitrypsin deficiencyEisenmenger's complexLAMAlveolar proteinosisSarcoidosis

IABP = intra-aortic balloon pump; LVAD = left ventricular assist device; ECMO =

extracorporeaJ membrane oxygenation.

COPO = chronic obslruclive pulmonary disease; LAM ':" Iymphangioleiomyo-

malosis

580 Ann. Surg. May 1996Van Trigt and Others

1.0

0.9

0.8

0.7

0.6

0.50.4

0.3

0.2

0.10.0

"iij>~~cn~

o 1 2 3 4 5 6 7 8 9

Survival Years

Figure 2. Kaplan-Meier survival estimate for cardiac transplant recipi-

ents

plantation included two patients with Eisenmenger'ssyndrome with biventricular failure, one patient withcomplex congenital heart disease (pulmonary atresiawith systemic collaterals to the lung, biventricular dys-function), one patient with sarcoidosis involving boththe heart and lungs, and one patient with cystic fibrosiswith a severely deformed right main pulmonary arteryand destroyed right lung.

RESULTS

Heart Transplant Recipients

The ischemic time for the 120 donor hearts was 148 :t7 minutes, with a range of 55 to 250 minutes. In the ma-jority ofthe patients, the Shumway atrioplasty techniquewas used for the atrial anastomosis. Later, patients weretransplanted using bicaval anastomosis to optimize rightventricu1ar filling and performance, and to reduce theincidence of bradyarrhythmias. Postoperative inotropicsupport was used to treat right ventricular donor dys-function commonly seen in the first 24 to 48 hours post-operatively.13 This usually consisted of low-dose epi-nephrine in combination with a phosphodiesterase in-hibitor. In selected patients with persistent pulmonaryhypertension and donor right ventricular dysfunction,inhaled nitric oxide at 40 to 80 ppm was used until extu-bation.14

There were ten postoperative deaths (8% operativemortality), with six due to allograft dysfunction, twofrom sepsis, one from postoperative pulmonary embo-lus, and one from bleeding and coagulopathy. ayer a 5-year period from late 1990 to mid 1995, there were nooperative deaths in 70 consecutive adult heart transplantrecipients. The estimated survival of the group is illus-trated in Figure 2, with a 1-year survival rate of90% anda 5-year estimated survival cate of80% (mean follow-up,5 years).

The length of post-transplant hospital stay was 23.8 :t4.0 days for the en tire group. Since the implementationof a post-transplant care map, the length of stay for thelast 25 patients has been reduced to 12.1 :t 2.4 days. Allpatients received at least one endomyocardial biopsy be-fore discharge, and cyclosporine dosing was stabilizedbefore release from the hospital.

Late mortality occurred in 11 patients from 1 to 7years after transplantation. Infectious complicationswere responsible for three deaths, whereas two patientsdied oflymphoma. To date, only two patients have diedof graft coronary artery disease. Hepatitis C, a rupturedaortic abdominal aneurysm, and a cerebrovascular acci-dent accounted for one death each. One patient died ofacute allograft rejection when he intentionally stoppedtaking cyclosporine 2 years after transplantation, in asuccessful suicide attempt.

Acute cellular rejection was assessed with surveillanceendomyocardial biopsies performed monthly for the first6 months then gradually decreasing in frequency to ev-ery 6 months by the third year after transplantation. Theprevalence of acute cellular rejection was 25% at 30 dayspost-transplant and 75% at the end of 1 year. We havefound a persistent, significant incidence of cellular rejec-tion of 15% to 20% per year after 3 years post-transplan-tation, which has led to the policy of continuing regularsurveillance biopsies late after cardiac transplantation.We have attempted to wean offprednisone by the thirdpost-transplant yearl5 and have been successful doingthis in approximately 50% of the patients. Cyclosporinedosing also is reduced gradually so that by year 4, thetargeted trough level is 100 ng/mL. If serum creatininelevels increase to more iban 3 mg%, cyclosporine dosingis reduced, and prednisone is reinstituted or increased.Acute rejection episodes are treated with methylprednis-olone (Solu-Medrol, Upjohn, Kalamazoo, MI) bolustherapy, with refractory rejection requiring rabbit anti-thymocyte globulin in a few patients.

Chronic allograft rejection in the form of graft coro-nary artery disease was assessed with coronary arte-riograms performed at least every 2 yearsafter transplan-tation. Stress thallium perfusion scans were performedon alternate years if the prior coronary arteriogramshowed no disease. Of 50 patients studied with coronaryarteriograms more iban 3 years after transplantation, 5had coronary lesions of greater iban 25% in one or morevessels (10% incidence). Two of these patients diedwithin 1 year of diagnosis (both 7 years post-transplanta-tion). The other patients have shown no clinical or ana-tomic progression of graft coronary artery disease.

Lung Transplant RecipientsSingle-Iung transplantation was performed through a

standard posterolateral thoracotomy incision with a

581Survival Benefits of Heart and Lung TransplantationVol 223. No. 5

Table 5. USE OF CARDIOPULMONARYBYPASS IN LUNG TRANSPLANT

PROCEDURES (N = 52)*

Procedure No.

Primary pulmonary hypertensionEisenmenger's complex (V80 patch)Pulmonary fibrosisCystic fibrosisCOPO

3/52/22/44/102/28

.Thirteen 01 52 patients required CP8.VSO = ventricular septa/ delect; COPO = chronic obstructive pulmonary disease;

CPB = cardiopulmonary bypass

plantation with lungs from a 66-year-old donar. Despitesupport with extracorporeal membrane oxygenation,ibis last patient died before retransplantation.

The mean length of stay was 23.4 days, with patientsdischarged before the first surveillance transbronchial bi-opsy ifthey were doing well clinically. All patients weredischarged to borne without oxygen therapy and wereentered into a 4-week program of pulmonary rehabilita-tion at an on-site location. Pulmonary mechanicsshowed significant improvement after transplantation,with FEV I increasing from 20% ofthat predicted to 60%of that predicted for patients with chronic obstructivelung disease.

Late deaths occurred in five patients, including bron-chiolitis obliterans in two patients who showed signifi-cant deterioration in FEV I at 5 and 18 months post-transplantation, and biopsy confirmed bronchiolitisobliterans in each. One patient each died from cerebro-vascular accident, acute rejection, and lung cancer origi-nating in the native lung of a single-lung recipient. Theestimated survival for the group of 52 lung transplantrecipients is illustrated in Figure 3, with a mean follow-up of 1 year.

Significant post-transplant pulmonary infections oc-curred in almost halfthe patients, with cy1omegaloviruspneumonitis occurring in ten patients. Because ofthe ag-gressive use ofprophylactic ganciclovir and cy1omegalo-virus hyperimmune globulin in at-risk patients, no pa-tients died of cytomegalovirus pneumonia. Bacterialpneumonia occurring early after transplantation oc-curred in eight patients, with Pseudomonas pneumoniadeveloping in four patients and methicillin-resistantstaphylococcal pneumonia developing in four patients.All were treated effectively with antibiotics except onepatient who died of Pseudomonas pneumonia 3 weeksafter single-lung transplantation. Adenoviral pneumoniadeveloped in two patients in the postoperative period,and both died. Two late infections with cryptococcal

1.0

0.90.8

0.70.60.50.4

0.3

0.20.10.0

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double lumen endotracheal tube. A telescopic bronchialanastomosis was used with 4-0 polydioxanone sutureand a modified interrupted figure-of-eight suture on thecartilaginous partían of the bronchus. An omental wrapwas not used. Significant bronchial anastomotic compli-cations occurred in two recipients, necessitating place-ment of an endobronchial silastic stent at the bronchialanastomosis. Bilateral sequential transplants were per-formed through a bilateral anterior (clam shell) thoracot-o~y incision with division ofthe stemum. Four patientshad lung transplantation through a previous thoracot-omy, two each in the single and bilaterallung groups.

Cardiopulmonary bypass was available for all proce-dures and was used in 13 of 52 patients (25%). Cardio-pulmonary bypass was used in both patients with Eisen-menger's syndrome receiving bilaterallung transplanta-tion and three of five patients with primary pulmonaryhypertension receiving bilateral lung transplantation.The remaining two patients with primary pulmonary hy-pertension were treated with inhaled nitric oxide duringtransplantation to maintain adequate oxygenation andhemodynamics until the first lung was replaced. Cardio-pulmonary bypass was used in other critically ill patientswho had significant pulmonary hypertension and ex-tremely limited pulmonary reserve, and in one patientwho had an associated coronary artery bypass graft X 1to the right cpronary artery at the time of right single-lung transplantation (Table 5).

The ischemic time of the donar lung in the single lunggroup was 3.5 hours, similar to the 3.6-hour ischemictime ofthe first lung in the bilaterallung group. The sec-ond lung in the bilaterallung group had a mean ischemictime of 5.5 hours.

Five patients died in the postoperative period, result-ing in an operative mortality rate of 8%. Two patientsdied ofadenoviral pneumonia, two patients died ofbac-terial sepsis, and one patient with severe pulmonary fi-brosis died of graft dysfunction after bilaterallung trans-

0.0 0.5 1.0 1.5 2.0 2.5 3.0Survival Years

Figure 3. Kaplan-Meier survival estimate lor pulmonary transplant recipi-

ents.

582 Van Trigt and OthersAnn Surg .May 1996

veloped in the first patient before the availability of apro-tinin. With the use ofaprotinin, two subsequent patientswho had undergone prior ventricular septal defect clo-suTe with persistent pulmonary vascular obstructive dis-ease and biventricular failure underwent successfulheart-lung transplantation. The second death in ibissmall population occurred in a patient with severe sar-coidosis involving both lungs and the heart. This patienthad an aspergilloma in the native right lung. He wastreated with amphotericin B post-transplantation, butstill died 3 weeks postoperatively of systemic aspergillo-SIS.

Table 6. HEART -LUNG TRANSPLANTRECIPIENT CHARACTERISTICS

Patient

Age (yr)

PatientGender Diagnosis Outcome

3817424230

MateFemaleMaleMaleFemale

DiedAliveAliveDiedAlive

Cystic fibrosis

Eisenmenger's complex (redo)Eisenmenger's complex (redo)Sarcoidosis. cardiomyopalhy

Congenital

DISCUSSION

This review of a single center's thoracic transplanta-tion program documents that heart and lung replace-ment in morbidly ill patients can be performed with lessthan a 10% operative mortality. In OUT small series ofheart-lung transplantation, the operative mortality wasmuch higher (40%), partially related to suboptimal pa-tient selection early in OUT experience with this proce-dure. The 5-year survival cate of 80% of OUT hearttransplant recipients compares favorably with the 70% 5-year survival cate in UNOS-compiled statistics. The lim-ited follow-up in OUT lung transplant recipients precludesestímate of a 5-year survival, but from other centers' ex-perience with longer follow-up, it appears that a 50% sur-vival cate at 5 years can be expected after lung transplan-tation.4

Because ofthe large number ofpatients with ischemiccardiomyopathy referred for cardiac transplantation andthe limited number of cardiac donors, which has not in-creased ayer the past several years, we systematicallyhave evaluated all patients referred for transplantationwith ischemic cardiomyopathy for coronary artery by-pass grafting using a careful preoperative assessment.18.19Using positron emission tomography scanning to deter-mine myocardial viability and right heart catheterizationto assess the degree of physiologic decompensation re-sulting from a low ejection fraction, high-risk coronaryartery bypass graft can be performed in selected patientswith an operative mortality of approximately 10%. Acomparison oflong-term survival of patients undergoingcardiac transplantation at Duke with a group of patientsundergoing surgical revascularization for ischemic car-diomyopathy is illustrated in Figure 4. ayer a 10-yearperiod, 118 patients with an ejection fraction less than25% (mean 21 %), underwent coronary artery bypassgraft?O This group had a high (68%) incidence of class 111or class IV congestive heart failure and was older thanthe transplant group. The survival curves quickly sepa-cate, and at 5 years postoperatively, the survival in thecoronary artery bypass graft group (60%) is significantly

pneumonia occurred, one in association with cytomega-lovirus. Both were treated with itraconazoleo

Acute lung alIograft rejection was diagnosed usingclinical criteria in the early postoperative period (de-crease in oxygenation, perihilar infiltrate on chest x~ray,drop in FEV1 > 10%, rever without evidence oforgan-isms in bronchial specimens) and by using surveillancetransbronchial biopsies in the late post-transplant pe-riodo Patients received three dally doses of Solu-Medrol500 mg for grade 2 or greater rejections, according to theIntemational Society for Heart and Lung Transplanta-tion classification.16 Acute cellular rejection docu-mented by biopsy occurred in 31 of 52 patients (60%),with most of these episodes occurring within the first 3months of transplantation during the first year. Half ofthose patients having histologic evidence of rejection hadmore than one episode of rejection confirmed by biopsyoSurveilIance biopsies were performed every 3 months af-ter transplantation, then every 6 months during the sec-ond year, and annualIy thereaftero

Chronic rejection in the forro ofbronchiolitis obliter-ans was confirmed histologicalIy in two patients at 5 and18 months post-transplantation. Each was a bilateral re-cipient, one with chronic obstructive pulmonary diseaseand the other patient with cystic fibrosiso The progressiveunrelenting course, characteristic of the syndrome, wasunaltered by augmentation ofimmunosuppression.17

Heart-Lung RecipientsClinical application of heart-Iung transplantation re-

mains at a low level because conditions previouslytreated with heart-Iung transplantation (primary pulmo-nary hypertension, cystic fibrosis, Eisenmenger's syn-drome with intact left ventricular function) currently canbe treated effectively with lung transplantation. Further-more, the allocation algorithm used by most organ pro-curement agencies is designed inherently so that a heart-lung block from a single donar will be divided to morethan one recipient. The clinical outcome of five patientsundergoing heart-Iung transplantation is shown in Table6. Severe, uncontrollable coagulopathy and bleeding de-

583Survival Benefits of Heart and Lung TransplantationVol. 2230 No 5

Figure 4. Estimated survival (Kaplan-Meier) for 118 patienls with ischemiccardiornyopathy treated with coronaryartery bypass graft cornpared with thecardiac transplant group. Also shownis Ihe model estimated survival formedical therapy afane.

o 1 2 3 4 5

Years

6 7 8 9

lung allograft. Bronchiolitis obliterans syndrome ap-pears to affect all subgroups oflung transplant recipientswithout distinction for age, sex, type of transplant, or un-derlying diagnosis. Because ofits proposed immunologicmechanism, most centers treat this with augmented im-munosuppression, but this usually is with minimal ben-efit. We have used an induction course ofrabbit antithy-mocyte globulin for 3 days post-transplantation in a ran-domized prospective trial to determine its potentialefficacyin reducing the long-term incidence ofbronchi-olitis obliterans syndrome.

CONCLUSION

Early and intermediate survival for heart, lung, andheart-Iung transplantation for one center is reviewed us-ing current techniques of organ procurement, pre- andpostoperative support, and cyclosporine-based immuno-suppression. Despite directing thoracic organ replace-ment to critically ill patients, so me requiring mechanicalcirculatory or ventilatory sUPPOrt' early survival is 80%to 90% at 1 year. The greatest risk to long-term survivalin these patients is chronic allograft rejection and dys-function.

Acknowledgment

lower than the survival in the transplant group (80%).However, ira pretransplant waiting list mortality rate of20% is taken into consideration, the overall efficacy ofeach treatment probably would approach the same sur-vival estimate. AIso shown is a model for estimated sur-vival with medicaI therapy alone using the COK propor-tional hazards method from a matched cohort of patientswith ischemic cardiomyopathy treated medically for cor-onary artery disease at Duke. The 38% 5-year survival inthis group falls well below either surgical group.

After surviving the wait for a donor organ, the mostserious risk to long-term survival faced by a heart or lungtransplant recipient is chronic rejection. In cardiac recip-ients, this is manifested by graft coronary artery disease.Although an immune mechanism is postulated in the eti-ology ofthis disease, mechanisms known to be involvedin atherosclerosis in nontransplant patients probably arealso involved.21 The relatively low incidence of graft cor-onary artery disease in this series (10%) compared withan often cited incidence of more than 30% at 3 yearspost-transplantation is not explained clearly. We havemaintained routine surveillance biopsies in an atiemptto reduce the contribution of rejection to this disease, aswell as careful follow-up and aggressive treatment of ele-vated lipids. We do not have intracoronary ultrasoundimages to quantitate intimal thickening, which might bepredictive of subsequent stenoses and death from graftcoronary artery disease.22

Bronchiolitis obliterans syndrome is the major causeof late morbidity and mortality in lung transplant recip-ients!3 The prevalence of this progressive and debilitat-ing disease is approximately 40%, usuaIly developing be-tween 15 to 30 months after lung transplantation. It rep-resents a chronic immune response directed against the

References

l. Frazier HH, Rose EA, Macmanus Q, et al. Multicenter clinicalevaiuation of the heartmate 100 IP left ventricular assist device.Ann ThoracSurg 1992; 53:1080-1090.

The autho~ thank Robin Ward for assistance in the preparation ofthis manuscript.

584 Van Trigt and Others Ann. Surg. May 1996

20. Milano CA, White WO, Smith LR, et al. Coronary artery bypassin patients with severely depressed ventricular function: determi-nants ofmortality and morbidity. Ann Thorac Surg 1993; 56:487-493.

21. Kobashigawa JA, Katznelson S, Laks H. Elfect of pravastatin onoutcomes after cardiac transplantation. N Engl J Med 1995; 333:621-627.

22. Valantine HA, Schroeder JS. Recent advances in cardiac trans-plantation. N Engl J Med 1995; 333:660-661.

23. Cooper JO, Billingham M, Egan T, et al. A working formulationforthe standardization ofnomenclature and for clinical staging ofchronic dysfunction in lung allografts. J Heart Lung Transplant1993; 12:713.

Discussion

DR. JAMES D. HARDY (Jackson, Mississippi): Dr. VanTrigt's results with bis colIeagues at Duke are superb; 1 congrat-ulate them. May 1 have the movie, please?

This movie presents the first lung transplant in man and thefirst heart transplant in mano This is the insertion of the firstlung transplant more than 30 years ago. We have anastomosedthe superior pulmonary vein, the inferior pulmonary vein, andthe pulmonary artery and now we wilI complete anastomosingthe bronchus.

This man had a carcinoma ofthe left lung which had blockedthe main stem bronchus, and had spread to bis chest walI aswelI. We are shown here taking blood samples to identify anddocument the fact that this lung that has just been inserted isperforming respiration effectively and it was.

Now 1 am going to stop the movie showing the first hearttransplant in man and show the first oftwo slides.

As seen, the first lung transplant was published in 1963(lAMA 186).

Next slide, please.This is the heart transplant we performed in 1964 (lAMA

188). And, Mr. Moderator, may 1 introduce three people? AIIright. 1 want to ask these three people to stand. The first is Dr.Carlos Chavez. Carlos, welcome. The next is Dr. Martin Dal-ton. And the third is Dr. George Walker. Dr. Chavez colIabo-rated on the first heart transplant, and Drs. Dalton and Walkerassisted with the first lung transplant.

Thank you very mucho

DR. PETER VAN TRIGT (Closing Discussion): 1 think 1 'd liketo express my gratitude to Dr. Hardy for sharing those historicmoments with us again. It is because of bis pioneering surgicalwork thirty years ago in col:11bination with the advances in im-munosuppression and advances in treating infectious diseasethat has alIowed us to achieve the survival benefits that we areable to do today. Thank you very much, sir.

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