Heart-Lung Transplantation for Irreversible Pulimonary Hypertension

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1 ORIGINAL ARTICLES Heart-Lung Transplantation for Irreversible Pulimonary Hypertension S. W. Jamieson, M.B., F.R.C.S., E. B. Stinson, M.D., P. E. Oyer, M.D., Ph.D., B. A. Reitz, M.D., J. Baldwin, M.D., D. Modry, M.D., K. Dawkins, M.B., J. Theodore, M.D., S. Hunt, M.D., and N. E. Shumway, M.D., Ph.D. ABSTRACT Combined heart and lung transplantation was carried out in 17 patients at Stanford University between March, 1981, and December, The recipients were between 22 and 45 years old. All patients had endstage pulmonary hypertension; ;LO had Eisenmenger s syndrome and the remaining 7, primary pulmonary hypertension. Five patients died within the first few postoperative weeks. The remainder are well between four weeks and 33 months from operation. The immunosuppressive protocol has consisted of cyclosporine with an initial coursc of rabbit antithymocyte globulin. Azathioprine also was given for the first two weeks and then was replaced with prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with high doses of methylprednisolone. Modifications of technique that have developed include the removal of the recipient heart and lungs separately, and l~reservation of the lungs with a modified Collins solution instead of a cardioplegic solution. Rejection occurred in 6 of the 12 survivors. Infections developed in 9 patients, but only one resulted in a fatal outcome (Legionella). Thus, the results of clinical heartlung transplantation have been considerably superior to clinical efforts in lung transplantation. It is suggested that the combined operation is preferable for the following reasons: (1) all diseased tissue is removed, thus eliminating recurrent infection and ventilatioidperfusion disparity; (2) transplantation of the entire heart-lung block preserves coronary-bronchial vascular anastomoses and makes airway dehiscence less likely; and (3) to date, diagnosis of rejection by cardiac biopsy has appeared to be a satisfactory method of diagnosing and taeating pulmonary rejection. Cardiopulmonary transplantation represents a viable therapeutic approach for patients with end-stage pulmonary hypertension with or without associated congenital heart disease. Demikhov [l] was among the first to perform successful experimental heart-lung transplantation operations. In the 1940s, he transplanted the heart and lungs in dogs From the Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, CA. The annual J. Maxwell Chamberlain Memcrial Paper, presented at the Twentieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 23-25, Address reprint requests to Dr. Jamieson, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, CA without the use of either hypothermia or cardiopulmonary bypass by making the appropriate vascular connections with the recipient s heart and lungs in place and later excluding them from the circulation. He constructed separate anastomoses for the right and left bronchi. Respiratory difficulties, notably related to the respiratory pattern, were responsible for death in the majority of dogs, and only 2 out of a total of 67 animals survived for 5 days. The heart and lungs are denervated after transplantation, and it became apparent that the dog was greatly dependent on pulmonary afferent nerves for respiratory control. In 1953, Neptune and colleagues [2] used central cooling with circulatory arrest to perform heart-lung transplantation in dogs, with survival for up to 6 hours. In 1957, Webb and Howard [3] reported six cardiopulmonary transplants using cardiopulmonary bypass in dogs, with survival ranging from 75 minutes to 22 hours. Again, a failure to resume spontaneous respiration was noted, and they suggested the possibility of cardiac and unilateral lung transplantation for clinical application t4, 51. In 1961, Lower and associates [6] achieved 6-day survival in dogs but noted that denervation led to increased tidal volumes and a slowed respiratory rate with long periods of apnea. Nine years later, Grinnan and coworkers [7] accomplished transplantation in 1 dog (out of 25) that lived for 10 days. These early experiments demonstrated that combined heart and lung transplantation was technically feasible and that a few animals would maintain enough spontaneous respiratory effort to survive for short periods. However, cardiopulmonary transplantation in dogs has never resulted in long-term survival. Haglin and co-workers [8] showed that denervation of both lungs was not compatible with long-term survival in dogs but that this was not the case in primates. Nakae and co-workers [9] also demonstrated a species difference in regard to pulmonary innervation, and reported that disruption of pulmonary afferent nerves in cats and dogs was not compatible with survival but that monkeys maintained a normal respiratory pattern. One of the first clinical heart-lung transplant operations was carried out in 1968, in a 2-month old infant with a complete atrioventricular canal defect [lo]. The child died 14 hours after operation, but it was noted that spontaneous respiration recurred. Another clinical transplant was performed in 1970 on a 43-year-old man with emphysema [ll]. He died of progressive respiratory failure after 8 days. A patient with chronic obstructive lung disease underwent combined heart and lung 554

2 555 Jamieson et al: Heart-Lung Transplantation for Irreversible Pulmonary Hypertension transplantation in 1971 [12]. The 49-year-old patient survived for 23 days after operation. In 1972, long-term survivors of cardiopulmonary transplantation were reported by Castaneda and colleagues [13], who studied autotransplants in baboons. Five of 25 animals lived as long as two years [14]. The advent of cyclosporine [15] as an immunosuppressant heralded the present era of successful cardiopulmonary allotransplantation. This drug provides superior immunosuppression to azathioprine and steroids combined [ 161 and allows adequate tissue healing. Thus, airway dehiscence, historically a major obstacle to long-term pulmonary allotransplant survival, is less likely. Long-term survivors after cardiopulmonary allografting in primates were reported by Reitz and associates [17] in Twenty-seven monkeys underwent cardiopulmonary transplantation using cyclosporine immunosuppression, and most survived for several months. Two of the monkeys remain alive today, almost five years after replacement of the heart and both lungs. Cyclosporine was first used in the ongoing program in clinical cardiac transplantation at Stanford in The clinical results [ 181, together with the laboratory experience with heart-lung transplantation in primates treated with cyclosporine, suggested that a clinical trial of combined heart and lung transplantation would at last be appropriate. Material and Methods Recipients There are many patients who might benefit from combined heart and lung transplantation. The first category consists of those who have damage to both heart and lungs. This includes patients with advanced pulmonary vascular disease, either Eisenmenger s syndrome or primary pulmonary hypertension. Pulmonary vascular disease is a chronic debilitating illness that is unresponsive to medical therapy in its terminal stages. The patients are usually young, in the third and fourth decades of life, and have marked functional disability. The occurrence of repeated syncopal episodes, hemoptysis, or both indicates a poor prognosis for 6- to 12-month survival. Many patients with Eisenmenger s syndrome have had one or more palliative operations, and most of those with primary pulmonary hypertension have had openlung biopsies. The adhesions caused by previous operations increase the risk of operation, since all patients have hepatic dysfunction and coagulation abnormalities, more marked in those with primary pulmonary hypertension because of tricuspid regurgitation. Also in patients with Eisenmenger s syndrome, large collateral vessels develop in the posterior mediastinum, which become less easily identifiable among the adhesions resulting from previous operations. The second category of potential recipients for combined heart and lung transplantation consists of those with irreversible disease of both lungs without major cardiac involvement. The operation could reasonably be applied to this group since the results of heart-lung transplantation are superior to those for lung transplantation alone. Included in this group are such patients as those with severe chronic obstructive airway disease, pulmonary fibrosis, cystic fibrosis, and other enzyme deficiencies. The combined operation in these patients would also avoid the problems that result from leaving one damaged lung in place, such as ventilation/ perfusion defects and a reservoir of infection within the chest. General requirements for prospective recipients are similar to those for patients having a cardiac transplant. Younger patients without other systemic illness and without severe secondary organ dysfunction have a better chance for survival and rehabilitation. Contraindications in our program include any active infection, diabetes mellitus, or extensive previous cardiac procedures. It is important that patients be psychologically stable and able to reliably follow a complex medical program. Apart from these broad indications of suitability, other more specific requirements are that the major disease process be isolated to the heart and lungs and that there not be serious hepatic or renal impairment. We have avoided recipients with a serum bilirubin level higher than 3.5 mg/dl or a creatinine clearance of less than 50 ml per minute. Postoperative treatment with cyclosporine requires these limitations, since this drug is metabolized almost exclusively by the liver and is toxic to both liver and kidneys. Because of the shortage of suitable donors, we have chosen, for the moment, to restrict potential recipients to those with pulmonary hypertension. Several factors make these patients favored candidates. There is always substantial cardiac involvement even in the primary form of this disease, and the patients are relatively young. The tracheobronchial tree is generally sterile, involvement of other organs is usually only the result of cardiac failure, and there is little likelihood of recurrence of the original disease. All 17 patients in the present series had end-stage pulmonary vascular disease with incapacitating symptoms. All exhibited a rapidly deteriorating clinical course resistant to conventional medical or surgical therapy. Ten of the patients had congenital heart disease and Eisenmenger s syndrome; 7 had primary pulmonary hypertension. There were 4 women and 13 men, rangmg from 22 to 45 years old. Cardiac catheterization revealed fixed high pulmonary vascular resistance. In the group with Eisenmenger s syndrome, 1 recipient had undergone multiple palliative surgical procedures, 1 had undergone pulmonary artery banding, and 1 had undergone ligation of a persistent ductus arteriosus. Four patients with primary pulmonary hypertension had undergone openlung biopsy. Donors Donors suitable for heart-lung transplantation are found less frequently than for renal or cardiac transplantation. Brain death may be accompanied by neurogenic pulmo-

3 556 The Annals of Thoracic :Surgery Vol 38 No 6 December 1984 nary edema or thoracic trauma, and prolonged ventilatory support may result in tracheobronchial infection. Probably only about 10% of potential cadaver donors have lungs suitable for combined heart and lung transplantation. Potential donors should be less than 35 years old. Compatibility with the ABO blood group and a negative cross-match between recipient serum and donor lymphocytes are required. Then! should be an absence of preexisting heart or lung disease, a close size match, and completely clear chest roentgenograms. The electrocardiogram should show no acute injury pattern. Satisfactory myocardial function with an adequate blood pressure without high-dose inotropic support should be present. Additional requiremlents include a satisfactory gas exchange, with an arterial oxygen tension of higher than 100 mm Hg on forced inspiratory oxygen of 40%, peak inspiratory pressures of less than 30 mm Hg with normal tidal volumes, and an absence of infected pulmonary secretions. The length of time that the patients have been ventilated is not as critical as the care that they have received during this time, and we have used donors who have been ventilated for as long as 5 days, whereas others have been unsuitable, as a result of pneumonic changes, on the day of death. The importance of size disparity between the transplanted lungs and the recipient s thoracic cage remains to be determined by further experience, but it seems clear that donor lungs that must be compressed to fit within the recipient thoracic case would develop severe atelectasis and pulmonary shunting. Whether a major mismatch in the opposite direction (the transplantation of small donor lungs into a 1arg;e thoracic cavity) would be as detrimental is unlikely, though we have noted the development of substantial pleural effusions when the lungs have been smaller than the recipient s chest cavity. The development of techniques for distant procurement will increase the number of available donors. Although satisfactory methods for heart preservation are available for a period of up to about 4 hours [19], techniques that reliably provide complete protection for lung tissue for this same period are not. A good deal of experimental work with single lung transplants has been reported [20, 211, but in initial experimental trials in our laboratory, application to the combined heart and lung graft has so far yielded unreliable preservation of lung function. We believe that distant lung procurement is not yet ready for clinical use, and at present, heart-lung donors are moved to the transplant center. Opera tion A most important aspect of the operative approach is to remove the recipient s heart and lungs without injury to the vagus or phrenic nerves or to the left recurrent laryngeal nerve. In addition, meticulous hemostasis with respect to the recipient s bronchial arterial circulation is essential, particularly in patients with Eisenmenger s syndrome in whom these vessels are especially large and delicate. i Fig 1. After removal of the heart, an incision is made through the oblique sinus to separate the right and left pulmonary veins. The vagus nerves lie immediately behind the pulmonary hilum on each side and anterior to the esophagus. The phrenic nerves are anterior to the hilum on each side, generally closer to the right hilum than the left. The left recurrent laryngeal nerve passes around the ligamentum arteriosum posterior to the pulmonary arterial bifurcation. The anatomy of the bronchial arteries is somewhat variable, but usually there are several large branches arising from the aorta and passing on either side posterior to the trachea and both bronchi. The size, friability, and relative inaccessibility of these vessels after implantation of the graft make their control critical. In the first 5 patients, the recipient s heart and lungs were removed together [22], but subsequent experience has shown that separate excision affords better visualization of the nerves and posterior mediastinal vessels [23]. The current practice is to remove the heart first, leaving a posterior cuff of both left and right atria. An incision along the posterior wall of the left atrium up the oblique sinus (Fig 1) allows separation of the lungs, and the left lung is then excised. The left side of the pericardium is removed except for a small ribbon containing the phrenic nerve. The right lung is removed in similar fashion, again preserving the right phrenic nerve. Then the remnants of the pulmonary artery are removed, leaving only a small segment in the area of the ductus ligament to avoid injury to the left recurrent laryngeal nerve. Finally, the trachea is exposed in the midline and divided just above the carina, and the bronchial remnants are excised. At present, our knowledge of lung preservation requires that the donor heart and lungs be removed in the adjoining room. Cardiopulmonary bypass is not required for this operation, and coordination is made with other transplant teams so that other organs can be removed. Prior dissection within the abdomen is carried out if required, and then the donor heart and lungs are exposed. After full-body heparinization, the superior

4 557 Jamieson et al: Heart-Lung Transplantation for Irreversible Pulmonary Hypertension quently. A certain amount of atelectasis is seen in all patients, and pleural effusions have been common, presumably contributed to by interruption of lymphatics on the posterior wall of the thorax. Fig 2. The tracheal anastomosis has been completed. A curvilinear incision is made in the right atrium, and the atria are anastomosed as shown. vena cava is ligated and divided, and the inferior vena cava is cut. After the heart has emptied, the aorta is cross-clamped and 500 ml of cold cardioplegic solution is infused into the aortic root. Simultaneously, 1.5 liters of modified Collins solution (high osmolality and high potassium) is infused into the pulmonary artery, and the tip of the left atrial appendage is amputated to allow egress of this fluid. Care is taken that the left ventricle does not become distended, and ventilation is continued using unwarmed room air. Implantation of the donor organs commences with the tracheal anastomosis, followed by the aortic and atrial anastomoses. The incision in the donor atrium is made in curvilinear fashion to avoid injury to the sinus node during implantation (Fig 2). All anastomoses are performed with continuous polypropylene sutures. After removal of air from the heart, ventilation is begun and the aortic cross-clamp is removed. Cardiopulmonary bypass is discontinued after a suitable period of resuscitation. Immediate postoperative care is similar to that of all patients who have undergone routine cardiopulmonary bypass except for the use of isoproterenol to provide chronotropic support (the cardiac output of the denervated heart is rate dependent) and the strict avoidance of high inspired oxygen concentrations. Immunosuppression is begun, and the patient is nursed in reversed barrier isolation. Extubation is accomplished early, and thereafter the patient is encouraged to cough and breathe deeply. Postural physiotherapy is used fre- Immunosuppression The regimen of immunosuppression that we have chosen for combined heart and lung transplantation begins with a preoperative dose of cyclosporine (18 mg per kilogram of body weight) and continues with oral administrations of cyclosporine twice daily for an indefinite period, as regulated by serum cyclosporine levels. We no longer use intravenous preparations of this agent. Immediately after discontinuation of bypass, 500 mg of methylprednisolone are administered intravenously, followed by 125 mg every 8 hours for a total of three doses. No further steroids are given for two weeks in an effort to avoid impaired tracheal healing. Cyclosporine immunosuppression is augmented for the first two weeks with azathioprine, given orally at a dose of 1.5 mg/kg/day, and an initial 3-day course of rabbit antithymocyte globulin (ATG) given intramuscularly. The dose of ATG is adjusted to reduce the circulating T- lymphocyte population to less than 5%. After two weeks, azathioprine is replaced with prednisone, 0.2 mg/kg/day administered orally. Patients with the original diagnosis of primary pulmonary hypertension require very small doses of cyclosporine, and the hepatic impairment of these patients is greatly exacerbated by cyclosporine administration. All patients experience a degree of renal dysfunction with cyclosporine therapy, and dialysis with plasma ultrafiltration has been required in 5 recipients as a temporary measure. Endomyocardial biopsy [24] is initially camed out on a weekly basis; after discharge from the hospital, it is done on a less frequent schedule depending on the clinical course. Rejection episodes within the first month, as diagnosed by cardiac biopsy, are treated with intravenous boluses of methylprednisolone (1 gm) daily for 3 days. Episodes of rejection resistant to this regimen are treated with additional rabbit ATG. After a month, rejection seems to be adequately treated by augmented oral steroids. We have not used additional techniques to diagnose pulmonary rejection, since our initial laboratory experience indicated that cardiac and pulmonary rejection proceed hand in hand (251. Recent studies indicate that this may not be an absolute rule and that it may be possible to encounter pulmonary rejection in primates without substantial cardiac rejection. Therefore, the concept of the cardiac biopsy providing an absolute prediction of the state of rejection of the lung might have to be tempered by the knowledge that pulmonary rejection can occur at a different tempo from that of the heart. The frequency and severity of rejection episodes as diagnosed by cardiac biopsy have been somewhat less following heart-lung transplantation than those observed with cardiac transplantation alone. A systematic review and comparison of cardiac biopsy specimens

5 ~ ~ ~~ ~~ ~ 558 The Annals of Thoracic Surgery Vol 38 No 6 December 1984 Data on 17 Patients Undergoing Heart-Lung Transplantation Patient No., Day of Sex, Age (yr) Diagnosis Rejection Infection Dischargeb 1. F, 45 PPH 2 Herpes (cutaneous) M, 30 ES 0 Cytomegalovirus (systemic) F, 29 ES X Not at risk for rejection or infection (4) 4. M, 40 ES 0 None F, 37 PPH 2 None F, 29 PPH X Not at risk for rejection or infection (23) 7. M, 22 ES X Not at risk for rejection or infection (0) 8. M, 40 ES 0 Bacteroides (blood and lung), M, 22 ES 2 cytomegalovirus (systemic) Enterococcus (lung) M, 28 ES 2 None M, 38 ES 0 None M, 33 ES 0 Cytomegalovirus (systemic) M, 33 PPH 1 Serrutiu (pulmonary), cytomegalo- 60 virus (systemic reactivation) 14. F, 28 PPH X Candida (systemic) (16) 15. M, 42 ES 0 Legionella, Serratia (33) 16. M, 22 PPH 1 Serru t ia M, 37 PPH 0 Enterococcus 64 Number of acute rejechon episodes occurrmg in the hospital and requinng intravenous administrahon of methylprednisolone bnumbers in parentheses represent day of death of the patient PPH = pnmary pulmonary hypertension, 1 3 = Eisenmenger s syndrome were made between 88 patients with cardiac transplants (treated with cyclosporine and prednisone, with the first 27 also receiving rabbit ATG) and 16 patients receiving heart-lung transplants (treated with cyclosporine and azathioprine and with a change to prednisone at two weeks). Evidence of myocyte necrosis (acute rejection requiring treatment) was seen in 299 (24.6%) of the 1,214 biopsy specimens from cardiac transplant recipients compared with 22 (13.8%) of the 160 specimens from heart-lung recipients (p < 0.001). Whether this is due to the different regimen of immunosuppression or to an inherent difference stemming from the transplantation of pulmonary tissue remains to be determined. The frequency of rejection episodes, as with cardiac rejection, is highest within the first 60 days after transplantation. Rejection episodes requiring one or more courses of augmented immunosuppression have occurred in 6 of the 12 long-term su::vivors, and resolution of rejection occurred in each with treatment. Nine patients have sustained serious :Infections (Table), although infection was responsible for the patient s death in only one instance. Additional details regarding the inhospital course of each patient are given in the Table. Loss of Pulmonary Innervation Transplantation of both lungs results in the loss of pulmonary innervation. It is unlikely that these nerves will regenerate, since reinnervation of allografted organs is rare [26], and in the fifteen years experience of the car- diac transplantation program at Stanford, no regeneration of cardiac autonomic nerves has been documented. The patients discussed in this report have provided the first opportunity to study the regulation of breathing in human beings in whom both lungs have been totally denervated. The recipient is immediately and probably permanently subject to other methods of regulation of breathing, but breathing patterns have been normal in most instances. Most, but not all, patients have maintained a carbon dioxide tension ranging from 45 to 49 mm Hg, especially immediately after operation. Regulation of breathing apparently occurs satisfactorily by way of chest wall afferent nerves, carotid body receptors, and inherent rhythmic control of breathing. During exercise, appropriate increases in minute volume, tidal volume, and respiratory rate occur, as found when the patients were studied 4 months postoperatively. Blood gases remain normal. Bronchial Arteries The healing of the airway anastomosis has been of major concern in lung transplantation. Unilateral lung transplantation has been plagued by bronchial dehiscence [27], and factors such as the length of the bronchial segment of the graft have been demonstrated to be important [28]. In single lung transplants there is no arterial vascular contribution from the donor side. In this respect, combined heart and lung transplants stand at a distinct advantage, since coronary-bronchial collaterals

6 559 Jamieson et al: Heart-Lung Transplantation for Irreversible Pulmonary Hypertension A Fig 3. Typical appearance of coronary angiograms from a patient 6 months after operation showing the collateral circulation from (A) the left coronary artery (arrow) and (B) the right coronary artery. can open up to restore vascularity to the vessels previously supplied by the bronchial arteries. Shortly after the operation has been completed, arterial bleeding can be seen from the cut surfaces of the donor pleural reflections and elsewhere. Necrosis, rupture, or late stenosis at the tracheal anastomosis has not yet been seen in the patients receiving a transplant to date or in the primate survivors of heartlung transplantation in our laboratory. In patients, coronary arteriograms made after operation have invariably shown the development of collaterals to the area of the suture line from the donor coronary circulation through atrial branches of the coronary arteries (Fig 3). Therefore, in human beings, the bronchial arterial supply directly from the aorta is relatively unimportant. The "Implantation Response" The postoperative management of patients with lung transplants is complicated by the development of impaired pulmonary gas exchange and the radiological appearance of interstitial edema about a week after operation. This syndrome, which is not present within the first few days after operation, has been termed the reimplantation response [27, 291, though we suggest the term implantation response for this phenomenon. The response is defined as a transient, reversible defect in pulmonary gas exchange, compliance, and vascular resistance and coincides with roentgenographic pulmonary edema early after operation. The cause is unknown, but it is likely that surgical trauma, ischemia, denervation, lymphatic interruption, and other pro- B cesses, exclusive of rejection, all contribute [27]. The entity is worrisome, although it resolves after a period of several days without specific therapy. It is absolutely vital, however, to differentiate this response from pulmonary rejection or infection. The finding has been described in animals and patients undergoing lung transplantation [27, 301 and in primates undergoing combined heart and lung transplantation [ 171, both allografts and autografts. The typical appearance of the implantation response in 1 of our patients is seen in Figure 4A; spontaneous resolution is shown in Figure 4B. A systematic review of the postoperative chest radiographs of the first 10 heart-lung recipients demonstrated the radiographic appearance of interstitial edema in all by the second postoperative week. It was not seen in 10 consecutive patients undergoing cardiac transplantation or 10 consecutive patients having coronary artery bypass. On the average, the radiological abnormality peaked on the eleventh postoperative day (range, 4 to 20 days). The pattern persisted for an average of 7 days (range, 2 to 12 days) and then resolved. Because of this tendency for pulmonary edema to develop during the first three weeks after transplantation, an aggressive diuresis is maintained, with the aim of achieving a negative weight balance early after operation. The 10 patients just mentioned had lost an average of 2.4 kg by the end of the third week. Severe oliguria (possibly a result of cyclosporine toxicity) necessitated hemodialysis with ultrafiltration in 5 patients. The implantation response is likely to be a reflection of increased capillary permeability or lymphatic interruption or both. Lymphatics probably regenerate after lung transplantation by the third week [20], thereby coinciding with the resolution of this process. The puzzling aspect of this phenomenon, however, is the lag period observed before its onset, since lymphatic interruption is present immediately. This delay might incriminate isch-

7 560 The Annals of Thoracic Surgery Vol 38 No 6 December 1984 A B Fig 4. Typical chest roentgenograms from a single patient. (A) Roentgenogram made 10 days after operution illustrates the implantation response. (B) One month later, th? condition has resolved without specific treatment. emic changes of the lung as the primary cause, with resolution aided by lymphatic regeneration. Results Twelve of the 17 patients are alive at intervals ranging from 1 to 30 months. Four patients died within 1 month of transplantation. One of them died on the fourth day as a result of severe hemorrhage B t the time of operation. She had transposition of the great vessels and pulmonary hypertension, and had undergone multiple palliative surgical procedures. Another had progressive renal and neurological impairment, and required dialysis and respiratory support until her dee th on the twenty-third postoperative day. One patient died during operation of a massive capillary leak phenomenon of the donor lungs, with failure of gas exchange and profound hypoxemia associated with pulmonary hypertension. Another patient died of progressive renal and hepatic failure and pulmonary sepsis on the sixtee nth postoperative day. This patient had severe prerenal azotemia and passive hepatic congestion preoperative ly, and these problems were greatly exacerbated in the early postoperative period. One patient died late. After an initially favorable course, he died of progressive pulmonary infection on the thirty-third postoperative day. Legionella was grown from the pleural fluid on the tenth postoperative day. Because of this rapid infection arid because the Legionella species was of a different strain from others encountered in our transplant population, it is possible that this infection was present in the donor lungs at the time of transplantation. The remaining patients have done well. Total cumulative survival following heart-lung transplantation now exceeds fifteen patient-years. All survivors have a normal exercise tolerance (New York Heart Association Functional Class I), and 9 patients who underwent repeat cardiac catheterization at one year had normal hemodynamics and normal pulmonary artery pressures. Two patients had repeat cardiac catheterization two years after transplantation, and the findings were again normal. The patients have maintained a normal functional capacity, and exercise freely and without limitation. The results of coronary arteriography have been normal, with the exception of the collateral arteries already described. Nine patients have survived more than 12 months after operation, and the first patient is alive and well nearly three years after operation. The long-term outlook for these patients remains uncertain. However, 2 monkeys in the laboratory studies apparently are well some four and a half years after heart-lung transplantation, without evidence of pulmonary hypertension or impaired gas exchange. Coronary artery disease is a complication often seen after cardiac transplantation, and it is likely that this will also be a potential complication after combined transplantation. The pulmonary vascular equivalent of coronary artery disease has not yet been seen, but probably can be expected to occur. Measures currently used to minimize this complication in recipients of a cardiac transplant may also be important in the combined transplant; they include antiplatelet drugs, low lipid diets, and regular physical activity. Five patients show evidence of early bronchiectatic changes, presumably a result of pulmonary denervation. Whether the main factor is large airway sensory loss giving rise to an impaired cough reflex or ciliary dysfunction is still being investigated. Continuing studies are focusing on improved control of the immune response, noninvasive methods of diagnosing rejection, mechanisms for changes in pulmonary

8 561 Jamieson et al: Heart-Lung Transplantation for Irreversible Pulmonary Hypertension vascular resistance and pulmonary epithelial permeability after transplantation, and the applicability of the technique to other clinical syndromes associated with advanced pulmonary disease. Comment Patients with end-stage pulmonary vascular disease pose a formidable therapeutic challenge. Those with Eisenmenger s syndrome are difficult to treat medically and cannot be treated with surgical procedures, including cardiac transplantation. Cardiopulmonary transplantation represents the only therapeutic avenue for these patients. Primary pulmonary hypertension is similarly difficult to treat medically, and is a progressive and fatal illness. Patients with primary pulmonary hypertension could theoretically be treated by unilateral lung transplantation, though this would leave them with only one functional lung. We believe that combined heart and bilateral lung transplantation is likely to prove a more successful approach. Advantages of the combined operation are that all diseased pulmonary tissue is removed, thus preventing both recurrent infection and ventilation/ perfusion imbalance caused by the remaining lung. A tracheal anastomosis, since it receives a better blood supply, is more likely to heal than a bronchial anastomosis; this is further aided in the combined operation since coronary-bronchial anastomoses in the en bloc graft are preserved. An additional advantage is provided by the ability to obtain sequential biopsies of the heart, since there appears to be a close correlation between cardiac and pulmonary rejection. Clinical experience with heart-lung transplantation has been encouraging to date and is considerably superior to that for unilateral lung transplantation. Currently the greatest problem confronting the program, the lack of suitable donors, for the moment precludes the application of combined heart and lung transplantation to many other conditions that involve terminal lung disease. References 1. Demikhov VP: Some essential points of the techniques of transplantation of the heart, lungs and other organs. In Experimental Transplantation of Vital Organs. Moscow, Medgiz State Press for Medical Literature in Moscow, 1960, chap 2, pp 29-48; translated from Russian by Basil Haigh, Consultants Bureau, New York, Neptune WB, Cookson BA, Bailey CP, et al: Complete homologous heart transplantation. Arch Sur 66:174, Webb WR, Howard HS: Cardiopulmonary transplantation. Surg Forum 8:313, Webb WR, Howard HS, Neely WA: Practical methods of homologous cardiac transplantation. J Thorac Surg 37361, Webb WR, de Guzman V, Hoopes JE: Cardiopulmonary transplantation: experimental study of current problems. Am Surg 27236, Lower RR, Stofer RC, Hurley EJ, Shumway NE: Complete homograft replacement of the heart and both lungs. Surgery 50:842, Grinnan GLB, Graham WH, Childs JW, Lower RR: Cardiopulmonary transplantation. J Thorac Cardiovasc Surg 60:609, Haglin J, Telander RL, Muzzall RE, et al: Comparison of lung autotransplantation in the primate and dog. Surg Forum 14196, Nakae S, Webb WR, Theodorides T, Gregg WL: Respiratory function following cardiopulmonary denervation in dog, cat and monkey. Surg Gynecol Obstet 125:1285, Cooley DA, Bloodwell RD, Hallman GL, et al: Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg 8:30, Lillehei CW: Discussion of Wildevuur CRH, Benfield JR A review of 23 human lung transplantations by 20 surgeons. Ann Thorac Surg 9:489, Barnard CN, Cooper DKC: Clinical transplantation of the heart: a review of 13 years personal experience. 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Heart Transplant 2:155, Modry DL, Walpoth B, Cohen R, et al: Heart-lung preservation in the dog followed by lung transplantation: a new model for assessment of lung preservation. Heart Transplant 2287, Reitz BA, Wallwork J, Hunt SA, et al: Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 306:557, Jamieson SW, Baldwin J, Reitz BA, et al: Combined heart and lung transplantation. Lancet 1:1130, Caves PK, Stinson EB, Billingham ME, Shumway NE: Percutaneous transvenous endomyocardial biopsy in human heart recipients. Ann Thorac Surg 16:325, Reitz BA, Gaudiani VA, Hunt SA, et al: Diagnosis and treatment of allograft rejection in heart-lung transplant recipients. J Thorac Cardiovasc Surg 85:354, Kondo Y, Matheny JL, Hardy JD: Autonomic reinnervation of cardiac transplants: further observations in dogs and rhesus monkeys. Ann Surg 176:42, Veith FJ: Lung transplantation. Surg Clin North Am 58:357, Pinsker KL, Koerner SK, Kamholz SL, et al: Effect of donor bronchial length on healing: a canine model to evaluate bronchial anastomotic problems in lung transplantation. J Thorac Cardiovasc Surg 77:669, Siegelman SS, Sinha SB, Veith FJ: Pulmonary reimplantation response. Ann Surg 17730, 1973

9 562 The Annals of Thoracic Surgery Vol 38 No 6 December Baranski EJ, Scicchitano LP, Camishon RC: Pulmonary hypertension following cardiopulmonary transplantation. Surg Forum 14:200, 1963 Discussion DR. BARTLEY GRIFFITH (Pittsburgh, PA): Aware of the early good results initiated by Reitz and co-workers and now confirmed by Jamieson and associates, my colleagues and I embarked on a similar program in heart-lung transplantation. During the last 18 months, we have evolved some different practices from those discussed by Dr. Jamieson. The differences include the selection of candidates, the maintenance of donors, a fear that the endomyocardial biopsy might not mirror lung rejection, and some concern about overimmunosuppression with respect to the development of lymphoproliferative disease. Candidates have included 3 patierits with pulmonary vascular disease, 1 patient with cystic fikrosis, 2 patients with obstructive lung disease, and 1 patient with eosinophilic granuloma of the lung. These patients have been accepted as a result of referral practice rather than a strong interest in pushing the limits of the operation. Although the patients with obstructive lung disease have not survived, all others have demonstrated early survival. The results certainly reemphasize the outstanding success and therapeutic nature of the operation for selected patients. We have found it easier to place donors on bypass. The bypass enables us to accomplish a relaxed removal of multiple organs including heart, lungs, liver, and kidneys, absolute hemostasis of the posterior heart-lung tiloc, and hypothermic lung preservation without flushing the pulmonary artery. Early in the series we used such a flush for procurement of lungs, thus relying on the flush of the pulmonaiy artery to cool and exsanguinate the lung. Subsequently, experimental canine and clinical human use of hypothermic (4 C) bypass has suggested that the flush is unnecessary and perhaps harmful for local procurement. Radiographs of recipients 4 months after transplantation demonstrate the hemostatic clips in the posterior aspect of the heart-lung bloc. We believe that much of the heralded postoperative hemorrhage occurs from the donor organ bloc rather than from uncontrolled vessels in the recipient. We have reservations about the endomyocardial biopsy always mirroring the rejection phenomena. We believe clinical rejection of the lung may occur with only minimal myocardial interstitial infiltrate. In one instance, simultaneous lung and heart biopsy specimens revealed scanty myocardial infiltration, yet there were desquamative macrophages in some of the air spaces and mild interstitial infiltration with round cells and fibroblasts. The lung tissue failed to grow infectious pathogens, but the recipient progressed to a fulminating lung failure. The differential diagnosis between rejection and viral infection can be difficult. Last, we are concerned about the potential for overimmunosuppression with multiple immunosuppressive agents including azathioprine, cyclosporine, and rabbit ATG. Among our 4 survivors, a lymphoproliferative disease developed in 2. We believe it is related to Epstein-Barr viral infection. In a lymph node removed from a patient 4 months after transplantation, the nuclear material was stained by immunofluorescence for the presence of Epstein-Barr nuclear antigen. The patient is free from clinical disease with reduction in immune suppression. It may be that we are overimmunosuppressing this group of patients, and I believe that in the future we will eliminate the early use of rabbit ATG and possibly even azathioprine. DR. JAMIESON: Thank you. I believe that the present era of successful transplantation, both of the heart and of the heart-lung bloc, is the result of the work of many, many pioneers. We are fortunate to be at the end of a long chain of such conscientious and industrious workers.