Lung transplantation

LUNG

TRANSPLANTATION

By 1980 rapid progress in the field of transplantation and related immunology established kidney, liver, and heart transplantation as appropriate procedures for selected persons with irreversible failure of these organs. Progress with lung transplantation, however, lagged behind, notwithstanding the considerable interest and research activity in the field since the late l!Mtts. The lack of progress can be attributed to several problems unique to the lung. The lung is a delicate organ with such intimate approximation of the air spaces and capillaries that even a relatively minor insult can cause significant dysfunction. Even temporary, potentially reversible derangement can jeopardize the survival of the lung transplant recipient who is dependent on the immediate function of the organ. Furthermore, techniques of lung transplantation have generally not included methods for restoration of the bronchial circulation. The resultant ischemia of the airway coupled with the exposure of the lung to airborne contamination increases the risk of infection, which is further enhanced by the posttransplant immunosuppression necessary to prevent rejection. After transplantation, lung dysfunction may be a consequence of ischemia, infection, rejection, or other factors associated with respiratory failure. The inability to correlate pathologic findings with specific etiologic factors greatly inhibited progress in both experimental The introduction of cyclosporine and clinical transplantation. brought an explosion of progress in the field of organ transplantation with significant improvement in the success rate of renal, carIts effect on lung transplantation diac, and liver transplantation.17’ has been even more dramatic, permitting successful grafting after nearly 20 years of failure. This monograph details the development of lung transplantation from early experimental animal work to the current state-of-the-art clinical application. HISTORY

OF LUNG TRANSPLANTATION

The first report of organ transplantation came from Vienna at the turn of the 20th century, when Emerich Ullman transplanted a dog’s Curr

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kidney from its normal position to the neck. This autotransplant worked well, but when he later transplanted a kidney from one dog to another, the kidney functioned only for a short time. Later still, Ullman transplanted a kidney from a dog to the neck of a goat, the first recorded xenograft.1s8 Ullman’s work was carried on by Alexis Carrel, who devised a surgical technique for reliably suturing blood vessels, an achievement that was recognized by the award of a Nobel Prize in 1912. Working with Charles Guthrie, Carrel successfully performed a kidney transplant in a dogz4 It was Guthrie who first performed a heterotopic heart-lung transplant, taking the organs from a kitten and placing them into the neck of an adult cat. This experiment was reported by Carrel in a lecture to the Johns Hopkins Medical Society in April 1906.“4 The recipient animal survived for 2 days. Further advances in thoracic transplantation awaited the development of positive pressure ventilation and a thorough understanding of cardiopulmonary physiology. As a general principle, successful lung transplantation requires that the sutured airway heal without stricture formation. Eloesser first demonstrated normal healing of a bronchial suture line in 1939 after performing a bronchotomy to remove an adenoma.4Y Taffel in 19401”” and Daniel in 1947”” resected segments of the main stem bronchus in dogs and demonstrated that portions of the aitway could successfully be replaced with various types of tissue. In 1949, Gebauer applied these techniques in humans to repair long segments of bronchial stenoses due to tuberculosis.GO Price-Thomas had earlier reported the first sleeve lobectomy and demonstrated successful bronchial anastomotic healing in humans.147 Demikhov, a Russian physiologist, successfully performed homografts of individual canine pulmonary lobes in 1947, but the Western world was largely unaware of this work until its translation and distribution in 1962.“’ Bellinazzo and Pulin performed autografts and allografts of canine pulmonary lobes in 1950.176 The autografts maintained function for longer periods than the allografts, which underwent rejection within 6 to 8 days. This was confirmed by Lanari the following year.““’ Most workers in the field of transplantation attribute the first lung autotransplant to Juvenelle.7”’ Y’SIS9 However, Metras, in France, actually published the technique of canine pulmonary allotransplantation a year before.‘lY Metras showed remarkable foresight, for he described a technique of harvesting and anastomosing the left bronchial artery to provide a systemic blood supply to the airway. He also described a left atria1 anastomosis, rather than separate pulmonary venous anastomoses. This technical feature was emphasized independently by Neptune in Philadelphia,l” who also documented 682

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improved survival after lung transplantation in dogs treated with adrenocorticotropic hormone (ACTHI. Consistently, early investigators documented a deterioration of graft function, which caused death of the recipient animal at about 7 days. This was attributed to rejection. Hardy observed that duration of survival in dogs undergoing single lung transplant could be almost doubled by treatment with methotrexate and further extended to a mean of 29 days if the animals were treated with azathioprine or azathioprine plus hydrocortisone.76 The ability of a transplanted lung to support an animal’s total respiratory requirement was documented in the early 1960s using a model that employed ligation of the opposite pulmonary artery, although extended survival was unusual.262 51,76 Hardy accumulated considerable technical experience in dogs76 before first attempting human lung transplantation at the University of Mississippi in 1963.78 Hardy’s patient, a 58-year-old convict serving a life sentence, had weight loss, hemoptysis, and fever. A squamous carcinoma almost completely obstructed the left main stem bronchus, with considerable volume loss in the left hemithorax. Because of significant emphysema in the contralateral lung and dyspnea at rest, it was believed that he was not a candidate for pneumonectomy. In addition, the patient had preexisting mild renal insufficiency and the nephrotic syndrome. A left lung transplantation was performed on June 11, 1963. The donor lung was harvested postmortem from a patient who sustained cardiac arrest after a massive myocardial infarction. At thoracotomy, the recipient had evidence of multiple pulmonary abscesses, secondary to his obstructing carcinoma. Metastatic disease was present in subaortic lymph nodes. A pulmonary arteriogram on the first postoperative day confirmed good perfusion of the transplanted lung. The patient survived 18 days, and death was attributed to renal failure and malnutrition. Autopsy failed to demonstrate any histologic evidence of rejection. Immunosuppression consisted of azathioprine and prednisone, supplemented with a &day course of cobalt radiation to the mediastinum. There was a small defect in the membranous portion of the bronchial anastomosis, but this was not believed to have significantly contributed to the patient’s demise. Hardy’s pioneering effort failed, but it established the technical feasibility of the procedure and showed that a transplanted lung could function in humans. This first attempt was soon followed by a transplantation of a single lobe for bronothers,lX3’ ‘I8 including chiectasis.16’ However, over the next 20 years in spite of nearly 40 attempts, no long-term clinical success was achieved. The most notable success, and the only recipient to feave the hospital, was a cut-r

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young man with silicosis who received a lung transplant by Derom and colleagues.” The patient survived 10 months, though most of this time was spent in the hospital. The lack of clinical progress led to further laboratory investigation into the technical and physiologic aspects of lung transplantation in an attempt to understand and overcome the barriers preventing successful lung transplantation. The first successful hea t transplantation in 196712 further stimulated general interest in the field of thoracic transplantation. Research centered on technical aspects of transplantation, pulmonary physiology after lung transplantation, and the effect of ischemia, denervation, loss of lymphatics, and loss of bronchial circulation on the reimplanted or transplanted lung. Several investigators confirmed the possibility of prolonged survival in animals after autotransplantation of a single lung, with minimal decrement in measured pulmonary function4’ “‘, ly6 Haglin confirmed that primates could survive for prolonged periods with a reimplanted lung by subsequently removing the remaining native 1ung.72 A variable increase in pulmonary vascular resistance in the transplanted lung was noted by many investigators. It soon became apparent that use of meticulous suture technique to avoid narrowing of the pulmonary arterial and venous connections produced almost normal pulmonary vascular resistance in the reimplanted lung.“, “, “, 2’3 Veith elegantly demonstrated that improvements in the technique of pulmonary artery anastomosis reduced the increase in pulmonary vascular resistance after reimplantation.z07 This lessened the concern that the increase in pulmonary vascular resistance might be an inevitable consequence of pulmonary denervation. The effect of pulmonary denervation in experimental animals was investigated by Nakae and co-workers from the University of Texas.‘“” In a series of experiments, progressive pulmonary denervation was accomplished surgically in dogs, cats, and rhesus monkeys. Nakae demonstrated that total cardiopulmonary denervation in dogs resulted in severe impairment of ventilation because of slow gasping respirations with prolonged periods of apnea. A similar pattern of ventilation was observed in dogs subjected to mediastinal dissection and division of the trachea. If the trachea was not divided, the mediastinal dissection resulted in a ventilatory pattern that was abnormal but was capable of sustaining life. Cats subjected to total pulmonary denervation also succumbed, but all the rhesus monkeys resumed a normal pattern of ventilation in experiments involving reimplantation of the heart and lungs.“” This implied a fundamental difference between primates and other quadruped animals with respect to the importance of pulmonary innervation. Subsequently, contralateral pneumonectomy after reimplantation of a lung was successfully demonstrated in baboons.72! go Several lx4

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groups had occasional success with bilateral lung transplantation in dogs,:‘, 15,2,’ Although the respiratory rate was frequently less than normal, ventilation proved adequate, indicating that pulmonary innervation was not absolutely necessary for survival in dogs. Despite the demonstration that nerve regeneration occurred across a reimplanted lung,‘“” the Hering-Breuer reflex did not return.lz7’ “’ Slim and colleagues reported survival after staged bilateral pulmonary reimplantation with a I- to 2-month interval between the operations.17J They later reported almost normal ventilatory responses to h-ypercapnia, hypoxia, and exercise in a long-term surviving dog almost 2 years after the second reimplantation.‘7” Evidence that humans could survive pulmonary denervation came from attempts to cure asthma by excision and reimplantation of the lungs.“’ These operations were accompanied by bronchial complications that were fatal in two instances. In the survivors, the asthma promptly returned. A transient interstitial edema accompanies lung reimplantation“ and is associated with decreased oxygen uptake out of proportion to the decrease in ventilation.” 7f’ The improvement in oxygen uptake parallels the reestablishment of pulmonary lymphatics. Hardy’s group demonstrated that this return of lymphatic function begins to occur 2 to 3 weeks after reimplantation.“” This also correlates with resolution of the increment in extracellular perivascular fluid that accumulates in reimplanted lungs.“’ The importance of the contribution of lymphatic disruption to pulmonary dysfunction is supported by the work of Bogardus, who showed that, after unilateral hilar stripping, the survival rate after contralateral pneumonectomy was drastically lowered because of interstitial edema in the remaining lung.‘” Reimplantation, however, has no effect on the amount or quality of surfactant.43’ 11” The importance of early reconstitution of the systemic arterial circulation to the autotransplanted lung escaped early investigators. In part, this stemmed from reimplantation experiments that clearly demonstrated reestablishment of systemic blood flow within 1 month5’ and perhaps as early as 10 days after reimplantation of a lobe.“’ In addition, no ill effects were noted after ligation of bronchial arteries in situ,77 although there was a recognized incidence of bronchial stricture or dehiscence after experimental lung autotransplantation.‘“” Mills and associates emphasized the importance of restoring bronchial artery blood ~upply.~‘~ He characterized four basic patterns of left bronchial artery anatomy in 50 canine autopsy studies. Based on this knowledge of the vascular anatomy, two groups of dogs underwent left lung reimplantation. In 10 dogs, a button of aorta containing the left bronchial artery was reimplanted with the lung. In 11 other control animals, no revascularization accompanied reimplantation. Eight of 10 animals in the revascularization group Cur-r

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had normal bronchial anastomoses at termination of the study, compared with only 2 of 11 animals in the control group. Despite this evidence, attempts to restore bronchial circulation were seldom employed in experimental or clinical lung transplantation. Veith developed a “telescoping” bronchial anastomosis in an attempt to reduce the incidence and morbidity of ischemic bronchial complications.‘“” As noted previously, experimental lung transplantation paralleled clinical attempts to achieve success. In 1970, Wildevuur and Benfield reviewed the accumulated world experience with lung transplantation,“‘Y Twenty-three lung transplants had been performed by 20 surgeons. Only Derom’s patient sunived longer than 30 days. This world experience included three lobar transplants, all of which were subsequently removed because of rejection. Most of the deaths in the collected global experience were attributed to respiratory failure, usually associated with infection. In the 16 patients who survived longer than 5 days it was not possible to distinguish between pulmonary infection and rejection as the cause of death. Veith, in an editorial, noted that “in view of the difficulty in suppressing human and canine allograft rejection . . . one might fairly ask if further attempts at human lung transplantation are justified.““’ Despite the dismal results, he believed the answer should be in the affirmative “in highly selected cases” and emphasized the need for more laboratory investigation to deal with issues relating to rejection and pulmonary function after lung transplantation. This was also the consensus of the first lung transplant workshop held in 1970.‘g5 By 1978 another 13 human lung transplant attempts had been reported, and all had been unsuccessful. During this time, however, considerable advancement occurred in the care of patients with acute respiratory failure: specifically, improvements in ventilatory support and hemodynamic monitoring, extracorporeal membrane oxygenator support, and fiberoptic bronchoscopy. Simultaneously, progress in transplantation of other organs was significant. At the University of Toronto, a decade of laboratory investigation led by F. G. Pearson and colleagues combined with expertise in surgery of the airways, successful application of membrane oxygenator support, and a strong interest in pulmonary surgery and respiratory intensive care prompted our initial attempt at clinical lung transplantation in 1978. The first patient was a El-year-old man with a 30% second-degree burn and a significant smoke inhalation injury. After 5 months of hospitalization, he remained ventilator-dependent. All attempts to wean the patient from ventilatory support failed, including therapy with prednisone. In spite of maximal ventilatoiy assistance the arterial Pco, gradually rose to levels greater than 100 mm Hg. A right lung transplant was performed under venovenous 686

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membrane oxygenator support. Postoperative immunosuppression consisted of azathioprine and prednisone (100 mg/day). During the first 2 weeks after transplantation, the patient was weaned from membrane oxygenator support, then from ventilatory assistance, and finally from supplemental oxygen. Vascular access sites and the thoracotomy incision healed poorly, and unfortunately, a bronchial dehiscence developed that proved fatal on the 17th postoperative day. Autopsy showed a 2-cm, full-thickness circumferential necrosis of the bronchus and lack of heating of the pulmonary artery or atrial anastomoses.12’ This discouraging result prompted us to review closely the experience of others. Of 20 patients surviving more than 7 days after lung transplantation, 16 had major complications relating to the bronchial anastomosis. We postulated that this failure in bronchial healing was caused by ischemia, rejection, immunosuppressive medications, or a combination of these factors, along with the detrimental effects of prolonged mechanical ventilation. With the aid of a number of research fellows from many countries, we began to systematically investigate the issue of bronchial healing after lung transplantation. It had been shown that steroids may inhibit wound healing,‘“” although in rats primary wound healing was not affected by prednisolone or azathioprine used separately or in combination8 To eliminate rejection as a variable, we performed left lung reimplantation in two groups of dogs. One group was treated with no immunosuppression, and the second group received methylprednisolone (2 mg/kg/day) and azathioprine (1.5 mg/kg/day) until death at intervals up to 23 days. In addition to lung reimplantation, four standard skin incisions were made in the back of each dog at the time of the lung reimplantation. An ellipse of skin containing a healing incision was harvested at intervals to assess breaking strength of skin wounds. The breaking strength of the bronchial anastomosis was measured at the time of sacrifice. Both bronchus and skin breaking strength were significantly reduced in the group of animals receiving immunosuppressive therapylo (Fig 1). Furthermore, animals receiving the immunosuppressive drugs showed a significantly higher incidence of disruption and necrosis of the bronchial anastomosis. This was convincing evidence that immunosuppressive protocols used for lung transplantation at the time could adversely affect healing of the bronchus. Subsequent studies of prednisone and azathioprine administered independently demonstrated that the prednisone alone was responsible for the poor wound healing. Azathioprine by itself had no adverse effect and did not potentiate the steroid effect. Using the same model of bronchial healing and skin wound breaking strength, we then tested cyclosporine, which had just become available, and Curr

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1800 1600

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FIG 1. Skin wound breaking strength in 3 groups of circles) had breaking strength similar to that Antmals receiving steroids (methylprednisolone), kg/day (triangles), had significantly reduced days. (From Lima 0, Cooper JD, Peters WJ, throprine on bronchial healrng following lung 1981, 8221 l-215. Used by permrssion.)

dogs. Dogs treated wrth cyclosponne (open of untreated control animals (closed circles). 2 mgikgiday, and azathioprine, 1.5 mgi skin wound breaking strength at 16 and 23 et al: Effects of methylprednisolone and azatransplantatton. J Thorac Cardiovasc Surg

found that animals so treated had wound tensile strength equivalent nicely to that of untreated animals.“” Scanning electron microscopy demonstrates the normal collagen organization after cyclosporine treatment contrasted with the deleterious effect produced by steroids (Fig 2). In the lung reimplantation experiments, we found that all animals had equivalent amounts of bronchial anastomotic stenosis, regardless of whether or not immunosuppressive drugs were administered. In almost all animals the anastomotic cross-sectional area was reduced by 25% or more when assessed 23 days after reimplantation. We felt this anastomotic narrowing might be related to bronchial ischemia. Previous work by Pearson and colleagues had docuFIG 2. Scanning electron micrographs of collagen from a normal bronchus (a) and from a bronchial anastomosis in an animal treated wrth methylprednisolone, 2 mg/kg/day, and azathroprine, 1.5 mgikgiday (b), contrasted with the normal appearing collagen of a bronchial 688

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anastomosis from an animal treated with cyclosporin Morgan E, et al: A comparison between cyclosporin thioprine on bronchial healing following canine lung vast Surg 1983; 85821-826. Used by permission.)

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A (c). (From Goldberg M, Lima 0, A and methylprednlsolone plus azaautotransplantation. J Thorac Cardio-

689

mented a high incidence of anastomotic stenosis after division and reanastomosis of the dog bronchus accompanied by interruption of the bronchial arterial circulation. Restoration of bronchial blood flow after division of the bronchus and reconnection required 2 or more weeks,140s 181 A similar time course to restoration of systemic bronchial flow had been shown in dog lung allografts.172 Ischemia had also been implicated as a cause of bronchial disruption by Veith and co-workers, who had shown that the length of donor bronchus had a direct bearing on the incidence of bronchial healing complications.14” In an effort to restore vascularization earlier, we performed bronchial omentopexy after left lung autotransplantation in dogs. Arterial circulation to the bronchus by means of collateral vessels from the omentum was restored within 4 days.log In addition to providing systemic blood supply, we believed that omentopexy might offer a margin of safety and prevent a bronchovascular or bronchopleural fistula in the event that bronchial healing was compromised after transplantation. The omentum previously had been used in thoracic surgery for protection of intrathoracic esophageal anastomoses,64 treatment of a bronchial fistula after lower lobectomy,210 or pneumonectomy.1g8 The utility of the omentum for other thoracic surgical problems has recently been reviewed.l” To assess the capability of the omentum to revascularize a totally ischemic bronchus, bronchial allografts were fashioned by performing a left pneumonectomy in dogs with division of the left main bronchus at its midpoint. The distal portion of the main bronchus along with the lobar bronchi was excised from the pneumonectomy specimen. The lobar bronchi were oversewn, and this distal portion of bronchus was reattached to the proximal main bronchus (Fig 3). This model eliminated any possible contribution of pulmonarybronchial collateral circulation and was done in five dogs, all of whom died within 5 days of complications of a gangrenous bronchial allograft with bronchopleural fistula. In eight other animals the ischemic stump was wrapped with omentum at the time of reimplantation. These dogs all survived and, when electively killed at 23 days, showed no evidence of bronchial necrosis, infection, or fistula formation with normal bronchial mucosa and cafiilage125 (Fig 4). This conclusively showed that the omentum rapidly restores blood supply to an ischemic bronchial suture line. The technique of omentopexy combined with the use of cyclosporine and azathioprine immunosuppression was applied to six dogs undergoing lung allotransplantation.44 Five of the animals survived 3 weeks and, at death, had adequate bronchial revascularization by omentum and, in all but one animal, no stenosis. Subsequent experiments using these techniques, with survival as long as 100 days or more, showed no bronchial complications and no late stenosis.‘63 690

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FIG 3. Model for creation of a totally ischemlc bronchial stump. Animals whose ischemic bronchial stumps were protected by omentopexy survived. (From Morgan E, Ltma 0, Goldberg M, et al: Successful revascularization of totally ischemlc bronchial autografts with omental pedlcle flaps in dogs. d Thorac Card/ovasc Surg 1982; 84:204-210. Used by permisslon.)

Similar results with cyclosporine in canine lung transplantation were also reported by other investigatorsY4 With the encouragement of these experimental results, it was decided to resume clinical lung transplantation. The initial attempt, in a patient with respiratory as well as multiorgan failure from paraquat poisoning, required a right lung transplant followed 3 weeks later by left lung transplant when residual paraquat damaged the first lung. Although gas exchange was excellent, ventilatory assistance was continued because of paraquat myopathy, and death occurred after 3 months without significant bronchial complication.‘“7 Patient selection for this procedure seemed to be of paramount importance. It was decided that the best potential recipients for the Cur-r Probl

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FIG 4. A, specrmen taken from a dog whose ischemic bronchral stump was protected by an omental pedicle flap. Even the mucosa of the bronchial stump was Intact. B, necrosis and gangrene were the consequence of an ischemic bronchial stump not protected by omenturn. (From Morgan E, Lima 0, Goldberg M, et al: Successful revascularization of totally ischemrc bronchial autografts with omental pedicle flaps In dogs. J Thorac Cardiovasc Surg 1982; 84:204-210. Used by permission.)

early efforts should be those with end-stage pulmonary fibrosis in whom life expectancy was deemed to be only a matter of months. On November 7, 1983, a right lung transplant was performed, using the omentopexy technique, in a B-year-old man with end-stage pulmonary fibrosis. Immunosuppression consisted of azathioprine and cyclosporine with the addition of prednisone at 3 weeks. The patient was discharged from the hospital 6 weeks after transplantation.lx8 Five and one half years later he remains active, works regularly, and has had no significant deterioration in lung functior.. A summary of our initial experience with single lung transplantation for end-stage pulmonary fibrosis has since been reported.18’ Success with single lung transplantation for pulmonary fibrosis stimulated interest in transplantation for other lung pathology for which single lung transplant would seemingly be contraindicated. This included bilateral pulmonary sepsis, such as cystic fibrosis, and end-stage emphysema. In 1981, Reitz and colleagues at Stanford University successfully performed combined heart-lung transplantation157 with repeated success in patients with end-stage right heart 692

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failure combined with increased pulmonary vascular resistance caused by primary pulmonary hypertension, or Eisenmenger’s syndrome. We and others141 subsequently employed the combined heart-lung technique for patients with end-stage pulmonary disease. It became apparent, however, that the majority of patients with endstage interstitial lung disease had adequate or reversible right heart function. We believed that unnecessarily replacing a recipient’s heart not only exposed the recipient to the acute and long-term problems associated with cardiac transplantation but also prevented use of the donor heart for another recipient. We considered the possibility of simultaneous bilateral lung transplantation, a procedure first proposed in 1970 by Vanderhoeft, who employed a right thoracotomy approach in d0gs.l”” In 1972 he subsequently reported block allotransplantation of both lungs using common pulmonary artery and left atrial anastomoses in dogs.“’ Another technique for double lung transplantation through a right thoracotomy without extracorporeal circulation was demonstrated by Grosjean and colleagues in 1976.“’ This approach, however, was not suitable for clinical application. Cadaver dissections confirmed the feasibility of performing en bloc bilateral lung transplantation via the median sternotomy route with the use of cardiopulmonary bypass. Initial short-term experiments using hypothermic circulatory arrest were carried out in puppies.37 After further experiments in primates, a successful double lung transplant was performed in a 42-year-old woman with end-stage emphysema secondary to alpha,antitrypsin deficiency.134 Two and a half years later the recipient remains in excellent health. The history of lung transplantation nicely illustrates the evolution from laboratory concepts and specific problem solving to successful clinical application. Much has been learned in the short time since lung transplantation became a clinical reality, and the knowledge continues to expand rapidly. LUNG REJECTION

AND TRANSPLANTATION

IMMUNOLOGY

A complete review of transplantation immunology is beyond the scope of this monograph; however, some specifics of pulmonary rejection warrant discussion. The cellular mechanisms of graft rejection may be subdivided into three phases: recognition, proliferation, and destruction. Recipient T-lymphocyte helper cells recognize antigens expressed on endothelial cells of a transplanted organ. The proliferative phase involves the return of these helper T-lymphocytes to regional lymph nodes where they stimulate the production of additional effector precursor cells such as T-effector cells and B-lymphocytes. These newly sensiCurr

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tized cells leave the lymph nodes and reach the graft via the bloodstream, where the destructive phase takes place. Activated T-killer lymphocytes lyse cells of the graft directly and release lymphokines that accelerate the rate of mononuclear cell infiltration. Activated B-lymphocytes differentiate to plasma cells, which produce antibodies specific to the graft’s antigens resulting in binding to the graft, complement activation, and destruction by polymorphonuclear leukocytes. Vasoactive peptides released by these interactions can alter blood flow to the graft, and platelet activation can result in the formation of intravascular thrombi. Persistence of donor lymphocytes and macrophages within the transplanted lungs of heart-lung recipients may stimulate strong allogeneic responses.“’ These donor cells remaining within the donor lung may also contribute to a limited graft-vs.-host-type response, a process that may augment rejection by the release of various lymphokines. Similarly, in the rat, observed peribronchial inflammatory activity is associated with graft lymphatic tissue referred to as bronchus-associated lymphoid tissue (BALT1.151 There is evidence that BALT lymphocytes (i.e., donor lymphocytes) are capable of accelerating the rejection response because the pretreatment of donors with a radiation dose of 10 Gy 1 day before transplantation demonstrated reduced immunogenic@ in an inbred rat model of lung transplantation.14” lsl Lung grafts depleted of all other passenger cells by retransplantation from a cyclosporine-treated intermediate host demonstrated even further reduction in immunogenicity.148 These observations further support the possibility that graft-vs.-host disease may be a feature of the rejection complex in lung transplantation. The histology of pulmonary rejection has been defined extensively in canine models but has not been well described for isolated lung transplantation in humans because of the limited experience. Rejection of the lung is manifest by a perivascular infiltration of mononuclear cells, accompanied by varying degrees of alveolar flooding and 10~s of ~e~~~~~~~5"~65~101'208~216 Veith has distinguished between the vascular and cellular changes and the predominantly noncellular “alveolar phase” of rejection, suggesting that these patterns proceed at different rates, depending on the use of immunosuppression. 171,208 The light microscopic appearance of perivascular infiltration with lymphocytes appears in dogs as early as the third or fourth postoperative day when no immunosuppression is used,lZ4 A typical appearance of rejection in a canine lung transplant is demonstrated in Figure 5. Survival of dogs in which transplantation was performed without immunosuppressive therapy ranges from 4 to 20 days, with a mean of 8 days.5”’ lol, ‘08 A similar time course of rejection of lung allografts has been observed in rats,“’ 17’ calves,18’ and primatesz2 ls7 In most canine experimental models of lung transplan694

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FIG 5. Light microscopic appearance of pulmonary rejection in a canine lung. Note the prominent perivascular mononuclear infiltrates. (Adapted from Saunders NR, Egan TM, Chamberlain D, et al: Cyclosporine and bronchial healing in canine lung transplantation. J Thorac Cardiovasc Surg 1984; 88:993-999.)

tation there is an absence of peribronchial activity, though this has been described in primate models” and rat models.‘5’ This predominance of perivascular inflammatory response corresponds to the localization, by immunofluorescent techniques, of immunoglobulin Ug)G and IgM depositions in subendothelial areas after canine lung transplantation.“’ Transbronchial lung biopsy was initially evaluated in the canine lung transplant model by Koerner but was found to be unreliable for the documentation of rejection when compared with open lung biand colleagues have pursued this technique in opsy.loo Higenbottam heart-lung transplant recipients.84 They have performed 43 transbronchial lung biopsies in 15 patients. Twenty episodes of rejection occurred in 11 patients, and biopsies showed typical changes of perivascular infiltrate and mucosal inflammation. One pneumothorax that required a chest tube for 2 days was the only complication among 43 biopsies. They reported no episodes of significant hemoptysis. Currently, no published data exist regarding experience with transbronchial lung biopsy after clinical isolated lung transplantation. Because of the concern of morbidity associated with transbronCurr

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chial lung biopsy, other less invasive methods of detecting allograft rejection have been proposed. Analysis of lymphocytes from bronchoalveolar lavage (BALI appears to be particularly promising. Dal Co1 and colleagues at the University of Pittsburgh have evaluated donor-specific cytotoxicity testing (DSC) in a canine single lung transplant model. Lymphocytes from the BAL grown in culture are assessed for DSC by testing their responsiveness to lymphocytes obtained from the spleen of the donor. Donor-specific cytotoxicity testing in BAL detected rejection in eight of nine dogs, even when the chest x-ray film result remained norma1.34 The same group has also used a primed lymphocyte test (PLT) in which BAL lymphocytes are incubated in culture with irradiated lymphocytes obtained from the donor’s spleen. An index of proliferation of lymphocytes is obtained by measuring the incorporation of tritiated thymidine, with proliferation representing the degree of alloreactivity present in a particular culture.67 Studies of BAL fluid in a canine model of single lung transplantation demonstrated that rejection was accompanied by an increase in the absolute number of lymphocytes recovered.‘l In addition, a cellmediated lympholysis assay showed more lytic activity in lymphocytes recovered from BAL fluid on the transplanted side than on the native (control) lung. This increase in cell-mediated lympholysis appeared to precede the radiographic changes of documented rejection.15” In a nonimmunosuppressed rat allograft model, an early increase in neutrophils (day 21 along with an increase in lymphocytes by day 4 occurred in BAL fluid. This increase in BAL lymphocytes was reduced by treatment with cyclosporin A.‘49 Subsequent studies showed that the earliest lymphocyte rise is related to an increase in T cells, followed by B cells, with an increase in neutrophils at a later stage coinciding with lung damage.‘“’ In human heart-lung recipients, observed proportions of macrophages, polymorphonuclear leukocytes, and lymphocytes are similar to the animal data. Unfortunately there has been an overlap in cell profiles noted during rejection and infection episodes.70 Cell-mediated lymphocytic activity increased in human BAL samples during rejection.6” However, the specificity of this response remains to be established. Zeevi has documented the presence of activated T cells in BAL fluid after heart-lung transplantation, but the presence of these cells did not correlate with clinical episodes of rejection.‘“’ Episodes of rejection were associated with an increase in the suppressor-cytotoxic cell population in BAL fluid, but similar increases in lymphocyte subsets were observed in the presence of cytomegalovirus or Pneumocystis infection.6s Moeschl from Vienna described a rosette-forming cell test (RFC) and indirect immunofluorescent test (IIF) in an attempt to ident$ 696

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cellular and humoral immune response activity in a canine model of single lung transplantation.lz3 Sections of the nontransplanted donor lung served as a target for indirect immunofluorescence. The earliest sign of organ-specific sensitization was detected with IIF on the fourth postoperative day. Immunoglobulin M antibodies showed higher titers than IgG only during the early postoperative period. The RFC test was used to detect recipient lymphocytes sensitized to the donor lung again 4 days after operation. Similar tests on dogs undergoing autotransplantation did not document any activity by IIF or RFC. Because of the ability to obtain donor lymphocytes from the spleen at the time of organ harvest, donor-specific assays may offer the most promise for the early identification of incipient rejection. The search for a serum assay of rejection, seemingly the simplest marker, is also complicated by the overlap of responses stimulated by rejection and infection, thus limiting the specificity. Soluble interleukin-2 (IL-21 receptor was shown to be elevated in human recipients of a lung or of a heart and a lung during clinically suspicious episodes of rejection.lo7 In six heart transplant recipients, levels of IL-2 receptor did not reflect rejection but increased during the first week after transplantation and during episodes of documented infection.180 Rejection in dogs after single lung transplantation is accompanied by reduced perfusion to the transplanted lung, which is documented with radionuclide perfusion scans.145 This implies that an increase in vascular resistance accompanies rejection. In dogs, urinary thromboxane B, has been recovered in larger amounts from animals with radiographic changes consistent with rejection after single lung allotransplantation.162 This may provide at least a partial explanation of the early changes in pulmonary vascular resistance observed clinically, though it is well recognized that thromboxane may be produced in the lung in response to a variety of stimuli.48 Although we have discussed lung rejection after isolated lung transplantation together with heart-lung transplanation, it is conceivable that the immune system responds to the two types of transplants differently. In support of this notion the incidence of bronchiolitis obliterans, a common development after heart-lung transplantation,‘l appears to be markedly less in patients who have received an isolated lung transplant. We are aware of only two cases of bronchiolitis obliterans after single lung transplant, both at other centers. Recent work suggests an immune-mediated mechanism operative in the development of obliterative bronchiolitis because, according to some investigators, the process may be attenuated by enhanced immunosuppression5, Is6 Whether obliterative bronchiolitis will become an issue in isolated lung transplantation awaits the accumulation of greater numbers of patients at risk for longer than 1 year. AfCur-r Probl

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ter heart-lung transplantation, the immune response engendered by the presence of both donor heart and lungs is different, as cardiac rejection occurs significantly less often than after isolated heart transplant and is not correlated with lung rejection.‘) 83 The detection of lung allograft rejection continues to be an area of intense research activity. The distinction between rejection and infection remains difficult, but the distinction is critical. Open lung biopsy remains the definitive test for rejection, but it is not practical on a day-to-day basis. Techniques using transbronchial biopsy or BAL are promising and may be done with minimum morbidity. INDICATIONS

FOR LUNG TRANSPLANTATION

With few exceptions, the indication for lung transplantation is irreversible, progressively disabling end-stage pulmonary disease. We have offered transplantation when, in our judgment, life expectancy is limited to 12 to 18 months. For most lung disease, however, specific clinical factors that allow for survival prediction are lacking, and one must make a judgment as to when to intervene. For purposes of discussing appropriate transplant operations, it is convenient to classify end-stage lung disease into the following categories: r-strictive, obstructive, infective, and associated with high pulmonary vascular resistance. The rationale for this categorization is that the choice of appropriate lung transplant operation is based on the effects of leaving native organs behind, the natural history of various end-stage lung diseases, and the effects of immunosuppression on this natural history. Selection for a single lung transplant, which usually may be performed without cardiopulmonary bypass, must be weighed against any potential problems caused by retention of the opposite native lung. The double lung operation is much more complicated, and we would prefer to resewe it for those in whom single lung transplant is contraindicated. Indications for each operation continue to evolve. RESTRICTIVE LUNG DISEASE Most single lung transplants have been performed for idiopathic pulmonary fibrosis or other restrictive disorders. The diagnosis of pulmonary fibrosis is usually established with a transbronchial lung biopsy or open lung biopsy performed in a patient with a history of progressive respiratory insufficiency, typical chest x-ray findings, and pulmonary function tests that demonstrate a significant reduction of lung volumes with preservation of flows. Diffusing capacity is usually markedly reduced. Idiopathic pulmonary fibrosis is associated with a 40% to 80% mortality within 5 years of diagnosis.97 A 898

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1989

profile of the first I1 patients with pulmonary fibrosis who received transplants shows a mean vital capacity of 41% predicted, a mean total lung capacity of 45% predicted, and diffusing capacity of 37% It is particularly difficult to predict length of survival predicted.l” for this group of patients, as there is a wide variation in progression of symptoms among patients. This makes it especially difficult to decide when to intervene with transplantation. It is helpful to follow the progress of these patients in a supervised program of pulmonary rehabilitation. A steady reduction in exercise tolerance or an increasing requirement for supplemental oxygen to prevent desaturation is an ominous sign, signifying further reduction in an already limited pulmonary reserve, and is an indication for intervention, assuming that the patient is otherwise a transplant candidate (see later). OBSTRUCTIVE

LUNG

DISEASE

Patients with emphysema, bronchiolitis, chronic bronchitis, and asthma fit into this category. These patients are often included under the term chronic obstructive puhonary disease (COPD).156 Emphysema is the underlying disorder of the majority of patients with obstructive disease presenting for transplant consideration. By conservative estimates there are more than 10 million Americans with some form of COPD; it is the fifth leading cause of death in the United States.85 Although many of these patients are elderly, especially those whose disease is related to chronic cigarette smoking, a considerable number could potentially benefit from transplantation. Severe life-threatening emphysema may occur during the fourth and fifth decades of life in individuals with alpha,-antitrypsin deficiency. There are more than 30 different biochemical variants of the alpha,-protease inhibitor. Humans are either heterozygous or homozygous for the gene responsible for the alpha,-protease inhibitor. Emphysematous changes have been associated with the homozygous type Z variant. The prevalence of homozygous type Z is estimated to range from 1 in 1,600 to 1 in 5,000 persons, but only a minority of these have end-stage obstructive respiratory disease.” Deficiency of alpha,-protease inhibitors is associated with a lack of protection against neutrophil elastase in the lower respiratory tract.58 Patients with this disorder may be excellent candidates for lung transplantation because of their relative youth and lack of involvement of other organs. It is not yet clear what effect the persistence of the alpha,-antitrypsin deficient state will have on the transplanted lung and whether recently available replacement therapy will be of value .‘I7 We have also seen young patients in the same age range with preCur-r

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699

mature end-stage emphysema who have normal serum levels of alpha,-antitrypsin. There are heterozygous phenotypes of alpha,-protease inhibitor that increase the risk of developing emphysema,88 and there may be other proteases that are important in protecting the pulmonary parenchyma from enzymatic destruction. Obstruction disease has been the underlying disorder in the majority of patients undergoing double-lung transplantation. The first six patients undergoing double-lung transplantation for COPD in our experience had a mean vital capacity of 47% predicted, a mean forced expiratory volume (FEV,) of 22% predicted, a mean total lung capacity of 145% predicted, and a mean diffusing capacity of 23% predicted.ZX As mentioned earlier, we initially believed that patients with obstructive lung disease were not candidates for a single lung transplant. The prospect of preferential ventilation of the remaining emphysematous, overly complaint lung causing air trapping with resultant compression of the lung graft was believed to be a distinct possibility. As perfusion will preferentially be directed to the transplanted lung because of its relatively normal pulmonary vascular resistance, a significant ventilation-perfusion imbalance might result. Early experience recorded in the literature with single lung transplantation for obstructive lung disease documented progressive alteration in the ventilation-perfusion ratio, but the extent to which the V/Q mismatch contributed to the patients’ demise remains unclear.‘77 Vanderhoeft reported a similar experience after a left single lung transplant in a 42-year-old man with emphysema whose postoperative perfusion lung scans documented increased perfusion to the transplanted lung, whereas radiographs documented a progressive volume loss on the transplanted side with expansion of the right emphysematous lung and mediastinal shiftZol The patient survived for only 10 days. Wildevuur reported 2 additional patients in whom compression of their transplanted lung by the native emphysematous lung developed.21” Veith also described 2 patients with emphysema who underwent single lung transplantation and who demonstrated radiographic evidence of a mediastinal shift toward the transplanted side.‘05 A summary of this early experience with single lung transplantation for chronic obstructive pulmonary disease is shown in Table 1. All of these transplants were performed in the precyclosporine era, and the contribution of rejection and infection to the poor outcome remains unclear. Recently, we have reassessed the application of single lung transplantation for obstructive lung disease. Andreassin and co-workers in Paris have performed several successful single lung transplants for patients with COPD.l14 Following this, we and others have performed single lung transplants in selected emphysema patients with 700

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1989

TABLE 1. Single

Lung

Transplant

for End-Stage

Obstructive

Pulmonary

Disease

Pre-1983

n

Survival >14 Days

Survivors

9 left

0

Suwival Days

>30

l/10

4110

10 1 right Compression

or significant

atelectasis

on chest

x-ray

616’

V/Q Scan

abnormal 4/4t

‘Data available on only 6 Patients. *Data available on only 4 Patients

excellent results. We feel that this approach is justified in selected cases, particularly in those situations in which double lung transplantation might be especially risky, such as in the patient aged more than 50 years, or in persons who have previously undergone unilateral thoracotomy or pleurodesis. We do, however, continue to recommend double lung transplantation for patients aged less than age 50 years with end-stage emphysema in the absence of contraindications, until such time as the additional accrual of data indicates which procedure produces the best long-term survival and functional result. INFECTIOUS

END-STAGE

LUNG

DISEASE

The primary focus of lung transplantation for this group centers around those with cystic fibrosis, a lethal inherited disease with an incidence of 1 in 2,000 live births in the United States. More than 98% of patients with cystic fibrosis die of pulmonary-related complications.164 In the lung the production of abnormally viscous mucus results in frequent infections beginning at an early age. Despite aggressive attempts at pulmonary toilet the cumulative effect of these repeated episodes is a progressive bronchiectasis-atelectasis that is accompanied by destruction of lung tissue and a gradual and irreversible decrease in pulmonary function. Destruction of the airway exceeds that of parenchyma so that the pulmonary pathophysiology is largely obstructive in nature. Patients with cystic fibrosis present particularly challenging problems to the transplant surgeon. In addition to the sequelae of chronic respiratory insufficiency, these patients often manifest nutritional depletion resulting from exocrine pancreatic dysfunction as well as from chronic infection. Because of the chronic pulmonary sepsis and colonization of the airways with antibiotic-resistant Curr

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701

gram-negative organisms, single lung transplantation is contraindicated. Chronic sinusitis is a constant feature in cystic fibrosis patients, and thus the potential for contamination and infection of the lower respiratory tract after transplantation with subsequent immunosuppression is ever present. Nevertheless, the experience of several groups suggest that these problems are not insurmountable. Yacoub and co-workers have performed 22 heart-lung transplants in patients with cystic fibrosis and have achieved a 70% l-year survival (M. Yacoub, personal communication). The Papworth group has reported 6 heart-lung transplants for cystic fibrosis with 5 operative survivors.1”8 Because the heart in most of these patients retains reasonable function, we believe the double lung transplant operation offers the most rational approach, as it preserves the recipient’s own heart and eliminates the acute and chronic problems associated with cardiac transplantation. Furthermore, the donor heart can be used for an appropriate heart transplant candidate. Yacoub has favored the so-called “domino procedure” in which the patient with cystic fibrosis receives a heartlung transplant and donates his heart to another recipient. PULMONARY

HYPERTENSION

For patients with pulmonary hypertension and car pulmonale the combined heart-lung transplant has generally been advocated. However, intervention with an isolated lung transplant before development of severe right heart failure may prove to be a rational approach. Primary pulmonary hypertension (PPH], a disorder of unknown etiologv in which the primary defect is increased pulmonary vascular resistance, usually strikes young, otherwise healthy persons (femaleto-male ratio, 1.7 : 1) .15' The natural history of PPH is quite variable, but the typical mean survival is 2 to 3 years from the time of diagnosis .5’7 Occasionally, patients survive for longer periods, but sudden death is not an infrequent manifestation of this disorder.“1”3 The course of this disease is one of progressive right heart failure that ultimately results in the patient’s demise. The traditional transplant approach for this group of patients has been combined heart-lung transplantation pioneered by the Stanford University Gro~p.l~~ The major issue in assessing patients with pulmonary hypertension for transplantation is the variability in survival. This was further confirmed by the Stanford Group, who reported on patients with PPH awaiting heart-lung transplantation.62 In a cohort of 90 patients, mean survival after diagnosis was 42.9 months. Fourteen of these underwent heart-lung transplantation a mean of 24 months after diagnosis. Because this disease is primarily a problem of increased afterload on the right ventricle, the question arises as to the degree of revers702

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ibility of the right ventricular dysfunction. Specifically, we have considered the possibility of single lung transplantation for patients with primary pulmonary hypertension based on experimental and clinical evidence that a significant degree of right ventricular failure is reversible.35’ 87 Those patients with secondary pulmonary hypertension resulting from volume overload of the lungs as a result of congenital left-toright shunts make up a second group of patients who potentially could be considered for lung transplantation. The pulmonary vascular lesions seen in this group are similar to those seen in patients with PPH.” Typically, these patients are seen late in the course of their disease because of the reversal of flow through a right-to-left shunt (Eisenmenger’s syndrome). As long as right ventricular function is compensated, it would be reasonable, in our opinion, to attempt single lung transplant and repair of the cardiac defect. In summary, we believe that candidates for lung transplantation should have end-stage disease with significant functional impairment that interferes with activities of daily living. Most of these patients require oxygen 24 hours a day. To further support the need for transplantation there should be documented evidence of disease progression with an anticipated life expectancy of 12 to 18 months or less without transplant intervention. Potential candidates need to be extremely well motivated to cope with the stresses associated with the preoperative and postoperative periods and with the lifelong care that they require after transplantation. Our selection critieria are summarized in Table 2.

TABLE Selection End-stage < 12No other

2. Criteria

for

Lung

Transplant

lung disease with 18 months systemic disease

No significant No evidence

Recipients

evidence

coronary artery of right ventricular

of progression

disease failure

(tricuspid

poor right ventricular contractility) Able to move to transplant center and Demonstrate compliance with medical

maintain regimens

No contraindication Psychologically

stable;

to immunosuppression no history of alcohol

Mobility: Must be ambulatory with Must not be on systemic steroids Single Lung Transplant

0,

Curr

Probl

SW..

regurgitation, self plus

or drug

October

lung disease bmnchiectasis,

1989

life expectancy

ascites,

support

abuse

Double Age

infectious bronchitis,

and

person

hepatomegaly, for

3-6

months

or psychosis

as required

Age < 60 years No chronic chronic

of disease

(e.g., CFJ

Lung

Transplant

< 50 years

No prior major pleumdesis

thoracic

surgery

01

703

EVALUATION

AND MANAGEMENT

OF POTENTIAL

CANDIDATES

Once a referral is initiated, basic data concerning the patient are collected by the transplant coordinator. The required data are summarized in Table 3. After initial screening, a decision is made to proceed with a formal in-hospital evaluation, to request more data, or to reject the patient from further consideration. Systemic steroids must be discontinued before consideration for lung transplantation because of the adverse effects of steroids on bronchial healing.108 It is often a lengthy and difficult process to wean these patients from steroids, and in some cases withdrawal of steroids may not be possible. We require patients to come to our center for detailed in-hospital evaluation, which allows for the entire transplant team to meet and further evaluate the patient. The in-patient evaluation is summarized in Table 4. Right heart function is assessed with right heart catheterization. Serial radionuclide right ventriculograms allow continued assessment of right ventricular ejection fraction in patients selected for transplant. All patients aged more than 46 years have left heart catheterization and coronary arteriography. The 6-minute walk test is a useful indicator of functional status and overall performance and is simply the total distance walked in 6 minutes. Oxygen is administered as required, 0, saturation is monitored with a portable pulse oximeter, and the patient can stop and rest as necessary. We quantitate the distance traveled and the maximal heart rate achieved and observe when and if the patient desaturates. The patients are also assessed on stair climbing ability and

TABLE Screening

3. Data

Medical: History Nature and progression of lung disease Smoking Prior surgery, especially abdomen, thorax Health in general Medications, including steroid histov Exercise tolerance Physical Examination Laboratory Arterial blood gases cl3c Electrolytes-BUN-Creatinine-Liver Function Tests Chest x-ray Pulmonary Function Tests Psychosocial Data 704

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1989

TABLE Lune

4.

Transolantation

In-oatient

Evaluation

Pulmonary assessment PFTS V/Q scan CT scan when indicated Cardiac assessment MUGA 2-D Echo Right Heart Catheterization, if suspect Increase PA pressure Coronary anigography All patients aged more than 40 years All double lung candidates aged more than 30 years Evaluation by social worker Consultation with clinical psychologist Psychological testing Assessment by physical therapist Defined 0, requirement at rest and with exercise Defined exercise tolerance 6 minute walk supetised with 0, treadmill saturation monitor 1 stair climbing Assessment by pulmonary rehabilitation Effective chest F’T Assessment by dietitian Ideal body weight Caloric intake

are asked to score their perceived dyspnea level during this activity. We value the input of our chest physiotherapists who conduct these functional studies. Assessment by both a social worker and psychologist is important for the recognition and evaluation of potential psychosocial problems that may preclude a successful long-term result. Patients who are accepted for transplantation are required to move to the area and are enrolled in an outpatient pulmonary rehabilitation program. Patients awaiting transplantation have often doubled their distance on the 6-minute walk test. It has been our experience that the conditioning provided by the pulmonary rehabilitation program allows for earlier weaning from the ventilator and facilitates postoperative ambulation. Patients with an exacerbation of their lung disease that requires hospitalization are temporarily taken off active status. Every effort is made to perform transplants only in those patients who are well enough to function in an outpatient setting, and we currently do not consider patients on mechanical venCurr

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1989

705

TABLE 5. Summary

of Referrals

for Lung

Transplantation

Distribution

of Diagnoses

Diagnosis

Number

Chronic obstructive lung disease Alpha,-antitrypsin deficient Cystic fibrosis Bronchiectasis Lymphangioleiomyomatosis Idiopathic pulmonary fibrosis Sarcoidosis Eosinophilic granuloma Other interstitial lung disease Primary pulmonary hypertension Secondary pulmonary hypertension

of Referrals 85 24 29 8 2 37 10 2 10 6 8

tilators. Contraindications to lung transplantation also include advanced age, active systemic disease, renal insufficiency, severe right ventricular dysfunction, significant coronary artery disease, psychological instability, or perceived inability to comply with the complex postoperative medication regimen. During the first 11 months of our lung transplant program at Washington University, St. Louis, there have been 210 referrals for transplant consideration. A summary of referrals by disease is presented in Table 5. Approximately 10% are accepted for transplantation. The main reasons for refusal are advanced age, steroid dependence, poor cardiac function, or technical considerations. As experience is gained in lung transplantation, indications for the procedure are likely to expand. THE

PULMONARY

DONOR

One of the limits to the widespread application of lung transplantation has been the scarcity of suitable lungs for implantation. It is estimated that organs are retrieved from only 20% to 30% of potential organ donors because of religious, social, or other reasons.‘” Probably only 5% to 10% of available donors have lungs that are currently considered acceptable for transplantation. Motor vehicle trauma is a common cause of fatal head injury, but blunt chest trauma with resultant pulmonary contusion is a frequent accompaniment. Aspiration is a constant hazard after head injury or any condition affecting the level of consciousness. Donors, who are by definition brain dead, require intubation and ventilation to be sustained, and this is associated with rapid colonization of the airway, which can lead to infection. After brain death, pulmonary 706

Cur-r

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1989

dysfunction146 and pulmonary edema are frequent occurrences, the latter possibly related to the outpouring of catecholamines.13z Because of these factors many potential donor lungs become unsuitable both before and after brain death has been declared. To reduce this loss, it is essential that optimal pulmonary care be administered from the time a potential donor is identified. This includes postural drainage, suctioning of the airway, judicious fluid administration, frequent monitoring of chest x-ray films and blood gases, sputum smear and culture, and if not contraindicated, 5 cm of positive end-expiratory pressure (PEEP) to replace normal physiologic PEEP that is lost with intubation. All of these “lung protective” measures in no way conflict with the optimal care of the patient who does not become a donor nor with the procurement of other organs should brain death occur. Our criteria for acceptance of donor lungs are, by design, somewhat rigid17 and are summarized in Table 6. Initially we request information regarding the chest x-ray film and evidence of adequate gas exchange, as evaluated with a Pao, of L 300 mm Hg on 100% oxygen and 5 cm PEEP. We ask that repeated assessments of arterial blood gases be performed every 2 hours. We hesitate to accept lungs when the arterial PO, continues to drop over time. Thoracic dimensions that we find useful are depicted in Figure 6 and are taken from a standard chest radiograph. In general we attempt to provide a prospective recipient with donor lungs that would be an appropriate size for that patient in the absence of his or her lung disease. For patients with pulmonary fibrosis, a lung larger than their native lung is chosen because considerable mediastinal shift occurs, the diaphragm is lowered, and the thorax expands to accommodate the new normal lung (Fig 71. In contrast, patients with COPD have an overexpanded chest cavity that will decrease in size when air trapping is no longer a clinical

TABLE 6. Lung

Donor

Criteria

Age < 55 years Normal chest x-ray Pao, 300 mm Hg on Fio,

1.0, PEEP 5 cm,

5 minutes Bronchoscopically

with

purulent secretions No significant chest contusion No previous thoracic

clear

no evidence

for of

or aspiration trauma or pulmonary surgery

on side

of

harvest

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1989

707

1

HORIZONTAL -

MEASUREMENT

Costaphrenic

angle to costaphrenic

angle

2 RIGHT VERTICAL -

3 l

Peak of diaphragm

to highest apical point

on x-ray

LEFT VERTICAL * Measure

in ccntcmcten

please

FIG 6. Chest measurements necessary Patterson GA: Assessing heart permisslon )

for assessment of a pulmonary and lung donors. Dagnosis

donor. (From 1988; 5:165-l

Boychuk 73. Used

JE, by

problem; hence lungs that are smaller by as much as 5 to 10 cm in vertical height and 5 cm in horizontal chest diameter have been used (Figs 8 and 9). The retrieval team brings along a copy of the prospective recipient’s chest x-ray film to permit on-site size comparison. If the predicted total lung capacity and vital capacity of the donor and recipient are similar, based on height, age, and sex, a satisfactory size match usually results for either single or double lung transplant. As for other organ transplants, lung transplantation requires ABO compatibility. We do not currently require HLA matching because the lungs might deteriorate during the time required for the matching, and there is currently no evidence to suggest that the results of 708

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1989

FIG 7. Left, preoperative posteroanterior (A) and lateral (B) chest x-ray films of a 20.year-old female with pulmonary fibrosis secondary to bleomycin therapy for Hodgkin’s disease who received a left lung allograft. Right, the posttransplant x-ray film demonstrates a shift of the mediastinum to the right, and the lateral film depicts the reexpansion of her chest cavity.

such matching significantly influence the long-term outcome, as is apparent for renal transplantation.161 The guidelines that we recommend for management of multiorgan donors are presented in Table 7. Management of the multiorgan donor is a complex problem, and one constantly needs to balance various pharmacologic interventions among the requirements of each donor team. From the standpoint of the lungs, fluid replacement should be kept to a minimum, as the lungs easily become edematous. We advocate the judicious use of vasopressors or low-dose doCorr

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1989

709

FIG 8. Left, posteroanterior (A) and lateral (B) chest x-ray film of a 42-year-old woman with alpha,-antitrypsin deficiency and end-stage emphysema. Right, after double lung transplant. Her diaphragms have risen and her cardiac silhouette has a different shape.

pamine to maintain blood pressure in the presence of adequate filling pressures. Because pulmonary function in the immediate posttransplant period is precarious, we do not believe that using wet lungs is safe and would prefer to abandon the proposed transplant if the alveolar-arterial oxygen gradient deteriorates during preparations for retrieval. Diabetes insipidus can be successfully controlled in most cases by the administration of vasopressin or DDAVP. Recent reports of improved donor stability via pharmacologic doses of thyroid hormone are intriguing, but to date we have had no experience with such therapy.131 719

Curr

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1989

Once the retrieval team reviews the chest radiograph and finds it acceptable, flexible fiberoptic bronchoscopy is performed. The presence of purulent secretions or evidence of aspiration contraindicates the use of the lungs. Material is obtained for culture and Gram stain at the time of this initial bronchoscopy. Results of the Gram stain are used as a guide to initial antibiotic therapy in the recipient. Additional cultures of the donor airway are obtained at the time of implantation. The final assessment of the donor lungs is direct inspection after opening both pleural spaces. The presence of pulmonary

FIG

9.

Left, preoperative

posteroanterior (A) and lateral (B) chest x-ray film of a Wyear-old man with end-stage emphysema. Right, after single lung transplantation on the left, there is some mediastinal shift to the left, but there is clearly adequate room for the newly transplanted single left lung in the oversized left hemithorax.

Cum

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1989

711

TABLE

7.

Guidelines

for Management

of Multiple

Organ

Donors

Maintain mean arterial blood pressure > 70 mm Hg Central venous pressure not to exceed -10 cm H,O and/or pulmonary capillary wedge pressure not to exceed -12 mm Hg Vasopressor support is preferable to massive infusion of fluid to maintain blood pressure Dopamine, 2.5 10 P.g/kg/min Phenylephrine, 0.06-0.18 mg/min ‘treat diabetes insipidus with vasopressin (5-10 units every 8 hr n/l or DDAVP (0.3 @/kg tV over 30 mint Fluid replacement: previous hour’s urine output plus 100 ml Maintain output l-2 ml/k#hr Replace electrolyte losses Maintain normothermia (35’ C to 37’ C) Pao, > 100 on lowest Fio, possible Maintain 5 cm PEEP Strict pulmonary toilet ABGs every 2 hr Elevate head of bed if possible

contusion or significant intrapleural adhesions would preclude lung donation. Only after this inspection does anesthetic induction of the recipient proceed. Though lung procurement in no way precludes other organ harvest, some delays are inevitable in any multiple organ retrieval. Close coordination with the recipient team is mandatory to minimize both the ischemic time of the lungs and the anesthetic time of the recipient. With current preservation techniques we strive to keep total donor ischemic time less than 5 hours. This constraint limits flying time between donor and recipient hospitals to 2 hours. HARVEST

OF THE

DONOR

LUNG

We have developed and described a method of lung extraction that does not interfere with the use of the heart for a separate recipient .lsl The procedure varies little for single or double lung extraction. Cardiectomy is completed before removal of the lung bloc, to avoid detaining the heart retrieval team. The key features include a left atria1 incision that leaves an adequate cuff on both the heart and lung bloc and the appropriate division of the pulmonary artery. To facilitate the left atrial division, the interatrial groove is completely dissected in the full, beating heart (Fig 10). This increases the margin between the right pulmonary veins and the atria1 septum and facilitates the left atria1 incision. The left atrial division is begun at the midpoint between the left pulmonary veins and the coronary sinus, with the heart retracted up and out of the pericardium and the apex directed toward the right 712

Curr

Pro61

Sung,

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1989

FIG 10. Development cardiac and

of the interatnal groove pulmonary transplantation.

greatly

facilitates

an adequate

left atrial

cuff for both q-

1m

shoulder (Fig 11). The orifices of the pulmonary veins can then be visualized from the inside, and care is taken to preserve a cuff of left atrium on the heart side as well as the lung side. Recognizing that the pulmonary artery proceeds in a posterolateral direction to the left allows for the accurate placement of the transverse incision in the pulmonary artery. The site is usually agreed upon between the lung and cardiac donor team and is approximately halfway between the pulmonary valve and bifurcation of the pulmonary artery. The initial incision is made in the anterior wall, after which the pulmonary valve and bifurcation may be visualized and used to guide the remainder of the incision. The left atria1 cuff and pulmonary artery stump that remain after transplant cardiectomy is depicted in Figure 12. It is our current practice to flush the lungs with cold electrolyte solution via the pulmonary artery. The site of cannula placement in the pulmonary artery coincides with the site of the subsequent division of the artery. The perfusate runs in under low pressure with the bag elevated no more than 30 cm above the level of the patient. Before flushing with the solution, prostaglandin E, (PGE,), 500 kg, is given by injection into the pulmonary artery over 60 seconds. This is done just before crossclamping the aorta. The tip of the left atrial appendage is excised to allow for venting of the left heart, whereas the Curr

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713

FIG 11. The left atrial incision is begun between the left pulmonary veins and the coronary sinus. The left atrial appendage stays with the cardiac graft. Once the atriotomy is made on the left side, the remainder of the atria1 incision over to the interatrial groove can be guided by the location of the right pulmonary veins as seen from inside the left atrium.

right heart is vented via a cut in the inferior vena cava. We clamp the inferior vena cava above the diaphragm and ask that the team retrieving the liver vent the aortic perfusate via a cannula in the inferior vena cava. During the instillation of the pulmonary artery flush, both pleural spaces are flooded with cold Eurocollins solution. To facilitate uniform distribution of the perfusate the lungs are ventilated during the pulmonary artery flush. The trachea is dissected and divided as far proximal to the carina as possible. Division of the innominate artery and vein facilitates this dissection. We divide the trachea between staple lines so as to pre714

Cum- mob1

sur5

October

1989

FIG 12. The inferior and superior venae cavae, ascending aorta, branches, and the left atrial cuff (forceps) are depicted

main pulmonary after cardiectomy.

artery

and

its two

vent flooding when the lungs are immersed for transport back to the recipient center. No attempt is made to dissect around the carina or at the level of either main bronchus. Both lungs are removed as a bloc that contains a left atrial cuff and the pulmonary artery bifurcation. The specimen is immersed in cold Eurocollins solution and is packed for transport. Taken in this fashion the bloc may then be prepared for two separate single lung transplants or kept intact for a double lung transplantation. These techniques can be modified for left single lung retrieval if only a single lung transplantation is contemplated. If this is the case, dissection in the interatrial groove is omitted and the right pulmonary veins can be divided as is usually done for a donor cardiectomy Curr

Probl

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1989

715

FIG 13. For harvest of a left single lung bloc, the right pulmonary veins can be divided in the usual fashion. On the left side an atrial cuff is required to facilitate pulmonary transplantatton, and the left atrium can be incised mldway between the left pulmonary veins and the coronary sinus as shown In the inset.

(Fig 13). The pulmonary artery is divided at the bifurcation, allowing the cardiac team to keep the main pulmonary artery in its entirety. The initial incision in the left atrium is made in a fashion similar to that described, that is, at the midpoint between the coronary sinus and the left pulmonary veins. The incision is then extended to the back wall of the left atrium rather than carrying it across to the right side. This leaves a small cuff of atrium around the left pulmonary veins for implantation of the single lung graft. The technique as described adds very little time to the extraction process, and most of the dissection is accomplished after removal of 716

Curr

Probf slq,

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1989

the heart so that cardiac extraction is not delayed. The actual retrieval of the lung bloc once the heart is removed takes an additional 15 minutes and is done while the liver and kidney teams continue working. LUNG PRESERVATION As it was uncertain how long the lung could tolerate cold ischemia, initial lung transplants were carried out with the donor and the recipient in adjacent operating rooms to minimize the ischemic period. The requirement for transportation of the donor greatly limited access to donor organs and complicated the logistics of the procedure. From animal experiments, it was apparent that cold ischemia, using simple immersion of the lung, was well tolerated for periods of 4 to 6 hours. Subsequent clinical application of this technique proved satisfactory, improving the supply of donor lungs and simplifying the logistics. The ability to safely preserve lungs for periods greater than 6 hours would have a significant impact on lung transplantation. Numerous experimental studies of lung preservation have been conducted, though with conflicting results.79.1Y3 Efforts have focused on whether and with what gas mixture the lung should be inflated, the optimal preservation temperature, organ perfusion versus flushing of the pulmonary circulation, and the constituents of the flush solution. Methods used to determine the quality of lung preservation include lung weight, measurement of lung water, histoloa, radiographic appearance, biochemical and metabolic changes, pulmonaty vascular resistance, and most common, assessment of gas exchange and overall survival after transplantation. Despite the development of various animal models, no standard method of assessing lung preservation currently exists, a situation that contributes greatly to the inconclusive or conflicting nature of many previous reports. Nonetheless, occasional graft survival with reasonable function occurs in animals after 24 hours of preservation, demonstrating the potential ability to prolong ischemic time.““, 144Jls4, lg2 Of particular interest are recent reports by Fujimura and co-workers of successful 48-hour preservation in a dog model using a flush solution of extracellular electrolyte composition containing a high concentration of phosphate buffer.“” In an animal model, it is difficult to assess function of a single transplanted lung because a normal contralateral lung remains. However, exclusion of the contralateral lung diverts all of the cardiac output through the transplanted lung, placing an abnormal burden on both this lung and the right ventricle. Futhermore, contralateral pneumonectomy or pulmonary artery ligation in dogs carries a high mortality unrelated to adequacy of preservation of the transplanted Cur-r

Probl

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1989

717

lung. Assessment of lung function after replacement of both lungs is ideal but requires primates for survival experiments because other species cannot maintain adequate ventilation after bilateral pulmonary denervation. To address this problem we developed a canine model that allows for in vivo, interval assessment of the function of a single transan inflatable pulmonary artery cuff planted lung.8” We position around the right pulmonary artery at the time of left single lung transplant. The inflatable cuff attaches to a subcutaneously placed reservoir, allowing for easy cuff inflation and temporary occlusion of the opposite pulmonary artery so that assessment of gas exchange and pulmonary artery pressure may be made with the normal, contralateral lung excluded. We have documented acceptable gas exchange immediately after and 3 days post transplant in dogs after 12 hours of donor lung ischemia following preservation by flushing with a solution similar to that proposed by Fujimura.Y8 The importance of inflation or ventilation of ischemic lungs remains unclear. Several researchers claim that ischemia is better tolerated at normothermia if the lung is ventilated or inflated.17’, ‘OSAt cold temperatures, ventilation with 100% oxygen may be detrimental,203 but recent experience with a rabbit lung model in our laboratory suggests that inflation with 100% oxygen may be superior to inflation with room air. Furthermore, storage of the lung in hyperbaric oxygen has also been reported as beneficial for preservation.“‘. y5 It is known that kidneys flushed with hypertonic solutions of intracellular electrolyte composition may be stored for 48 hoursz7, ltio This knowledge prompted the use of similar solutions with a high potassium content for pulmonary flushing experiments. Adequate long-term lung function has been sporadically achieved after ischemit periods of up to 24 hours with use of this type of so1ution.142 Similar success occurred in a canine allotransplant model using Sacks solution.3”’ ‘04 Primates undergoing heart-lung transplantation after pulmonary flushing with Eurocollins solution and cold ischemia for 5 to 6 hours also had adequate pulmonary function.155’17” Several centers report safe preservation of human lungs for up to 4 hours using a cold electrolyte flush solution preceded by injection of prostacyclin or PGE, into the pulmonary artery. The latter substances are pulmonary vasodilators and probably improve the uniformity and efficiency of distribution of the cold electrolyte flush so1ution.214 Either flushing donor lungs with Eurocollins solution or core cooling with an extracorporeal circuit without flushing provides acceptable gas exchange after heart-lung transplantation in dogs.212 However, of the two methods, core cooling results in lower pulmonary vascular resitance immediately post transplant. Core cooling is a reasonable method of preservation for calf lungs for up to 4 hours of 718

Curr

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1989

ischemia before transplantation’“’ and has been used widely in England by Yacoub and co-workers for clinical heart-lung transplantation.“’ Autoperfusion of the heart lung bloc represents an alternate method of heart-lung preservation.‘04 Early animal experiments with this method were encouraging, and pulmonary function after calf heart-lung transplantation compared favorably with pulmonary function after hypothermic flushing with Collins solution in the same model.’ Clinically, however, this method is inconsistent and complicated and is no longer used. It is currently believed that lung injury in donor organs results not only from the ischemic insult but also from injury occurring at the time of reperfusion of blood through the preserved organ. Several experimental models of acute lung injury implicate oxygen free radicals in the genesis of reperfusion injury.“7”33 Several mediators, including prostaglandin metabolites, play a role in the vascular and bronchial smooth muscle response to injury in the lung.40 It is likely that some of these mediators are also important in the lung’s response to ischemia. Ischemia-reperfusion injury in other organs is associated with lethal calcium influx, and thus calcium channel blockers, such as verapamil, may offer some protection against warm ischemia in canine lungs.71 Enhanced tolerance to ischemia also results from infusion of prostacyclin analogue (PGIJ in a model of in situ canine lung ischemia and autotransplantation.“* Prostacyclin infusion improved pulmonary function in acute heart-lung transplants in dogs.‘l Ischemic injury in isolated, perfused canine lobes is reduced after pretreatment with superoxide dismutase (SOD)lo3 or SOD and catalase given upon restoration of blood flo~.‘~~ Superoxide dismutase has been shown to enhance preservation in an acute model of canine heart-lung transp1antation.l’ Similarly, the free radical scavenger glutathione added to Eurocollins flush solution reduced the increase in lung water that usually accompanies canine pulmonary autotransplantation,” and dimethylthiourea has been shown to have a beneficial effect as we11.13’ Despite satisfactory results with the dog transplant model, such a model is expensive, time-consuming, and less than ideal as a screening method for testing the many factors relating to lung preservation. We have developed an isolated, perfused rabbit lung model to rapidly screen preservation techniques such as storage temperature and perfusate composition.21s With this model we demonstrated that lung preservation at 10" C is significantly better than preservation at 4" C. Others note that this storage temperature may be optimal for cardiac preservation as well.‘” Using a model of isolated perfused rabbit lungs, Breda and co-workers showed that lung function was improved if preserved lungs were reperfused with leukocyte-depleted bloodl’ or if the perfusate contained methylprednisolone.73 Curr

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719

TABLE

8.

Methods

of Lung

Preservation

Hypothermic immersion With atelectasis With inflation With ventilation With hyperbaric oxygen Normothermic perfusion Autoperfused heart-lung preparation Hypothermic perfusion Core cooling, with or without perfusion Flushing Extracellular fluid solutions Low potassium dextran Fujimura Ringers, saline Plasma, blood Rheomacrodex Intracellular fluid solutions Collins Sacks Pharmacologic additives Prostaglandins: PGI, Clacium channel blockers Free radical scavengers: SOD, catalase,

glutathione,

DMSO

Most experimental studies in lung preservation to date have been largely empiric, evaluating the effect of various preservation techniques on subsequent lung function. These are summarized in Table 8. Further progress requires a more detailed understanding of events at the cellular level during ischemia and reperfusion so that a rational approach to reduce or eliminate these changes may evolve. Satisfactory preservation techniques must protect not only cell structure and metabolism but also functional integrity of the lung as a whole, so as to maintain normal gas exchange. In addition, methods that allow for prolongation of ischemic time must also preserve the viability and microcirculation of the airway to prevent the subsequent complications of airway healing. Given the current ability to safely preserve livers and kidneys for 24 hours or more, it seems likely that lung preservation for up to 12 hours will become a reality in the near future. TECHNIQUE

OF LUNG

UNILATERAL

LUNG

TRANSPLANTATION

TRANSPLANT

OPERATION

Our technique of lung transplantation approximates that initially reported by Metras in France in 195Ol’” and subsequently by Hardin 720

Curr

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1989

and Kittle

in the United

States,75 with

the addition

of bronchial

omentopexy as previously noted. We applied these techniques initially in the animal laboratory and in multiple cadaver procedures before implementing our clinical program. We have previously puboclished our techniques,2Y’ 15’ but minor revisions are constantly curring. Transplants have been performed on either side with equal success, though we prefer the left side, if possible, as it is easier to achieve adequate recipient left atria1 cuff and the recipient pulmonary artery and bronchus are longer and easier to prepare. Furthermore, it would appear that an oversized lung may be more easily accommodated on the left because of mediastinal shift and easier descent of the left hemidiaphragm. We provide here a brief review of technical features. The choice of which side to transplant also is dependent on several factors: (1) prior major thoracotomy-transplant nonoperated side; (21 significant disproportion of ventilation and perfusion to one side-transplant the worse side; (3) donor factors-transplant the best donor lung, if there is concern as to radiologic or bronchoscopic findings of one of the lungs.

Anesthetic

Technique

Our anesthetic management for single lung transplant recipients has been recently outlined.“8 Preoperatively, a pulmonary artery catheter is positioned in the contralateral lung. Additional monitor-

ing includes

pulse oximetry,

arterial

pressure,

and continuous

end-

tidal CO,. An extracorporeal bypass circuit incorporating a membrane oxygenator is primed and available in the room on a standby basis should partial bypass prove necessary while the patient is being supported by only one lung. For most transplants this has not been required. Patients undergoing left lung transplant have

a bronchus-blocking

balloon

inserted

into the distal trachea

before

intubation with a standard endotracheal tube. The inflatable balloon is then positioned in the left main stem bronchus under bronchoscopic guidance. For patients undergoing right lung transplant, we

insert

a left endobronchial

tube and confirm

the placement

with a

pediatric flexible bronchoscope. The patient is placed in the lateral decubitus position and the chest, abdomen, and ipsilateral groin area are prepared and draped. With the patient in the supine position, we previously began the

procedure

by performing

dominal closure lateral decubitus

Surgical

the omental

mobilization

followed

by ab-

and repositioning the patient. We now prefer position for the entire procedure.

the

Technique

Through an upper midline abdominal incision we mobilize the gastrocolic omentum off the transverse colon and create a retrosternal tunnel. The apex of the omentum is placed in the retrosternal Cur-r

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October

1989

721

FIG 14. The left pulmonary artery are taken extrapericardially

is divided distal to tts first branch, for the recipient pneumonectomy.

and

the left pulmonary

veins

region for subsequent positioning into the pleural space. The thoracotomy is performed, and the main pulmonary artery is isolated and temporarily clamped. If the trial clamping of the pulmonary artery causes a significant rise in pulmonary artery pressure, infusion of a pulmonary vasodilator, such as nitroprusside, or PGE, is used in an attempt to reduce the pulmonary vascular resistance and right heart strain. If this is not well tolerated, the femoral vessels are prepared for subsequent partial venoarterial bypass during replacement of the lung. If the trial clamping of the pulmonary artery is well tolerated, the clamp is removed and the remaining hilar structures are dissected and removed. The pulmonary artery clamp is then replaced, and the pulmonary artery is divided just distal to the first branch. The artery is trimmed back at the time of pulmonary artery anastomosis. The pulmonary veins are divided between ligature outside the pericardium (Fig 14). The bronchus is divided just proximal to the upper lobe takeoff. The inflated bronchus-blocking balloon maintains a sealed airway. Alternatively, the bronchus can be divided just distal to a staple line with subsequent resection of the staple line and in-

722

Curr

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1989

FIG 15. After orienting the donor lung a running suture. The bronchus

in the left chest, the left atrial anastomosis is occluded with a bronchus-blocking

is performed with balloon in its lumen

flation of the balloon at the time of the bronchial anastomosis (Fig151. After the lung has been removed, the pericardium is opened around the pulmonary veins and a left atria1 clamp is placed as central as possible without impinging on the contralateral pulmonary veins. The previously placed ligatures are removed from the stumps of the two pulmonary veins, and a suitable left atrial cuff is prepared by incising between the two venous orifices. Preparation of the donor lung commences before implantation, with division of the bronchus two rings above the upper lobe takeoff and division of the pulmonary artery at its origin from the common pulmonary artery. A cuff of left atrium remains around the pulmonary veins from the time the donor heart was extracted before lung extraction. The lung, wrapped in cold moist laparotomy sponges, is placed posteriorly in the chest. The posterior wall of the atria1 anastomosis is performed first with subsequent completion of the anterior wall. The donor and recipient arteries are trimmed to suitable lengths and an end-to-end anastomosis is performed with running

Cow

Probl

Surg,

October

1989

723

FIG 16. After completion of the bronchlal anastomosis the bronchus and secured loosely.

the omentum

is completely

wrapped

around

monofilament suture. Upon completion, the pulmonary artery anastomosis is left untied temporarily. The bronchial anastomosis is performed with interrupted absorbable sutures. The left atria1 clamp is then gradually removed, and the pulmonary artery anastomosis is observed for back-bleeding, which usually occurs after 3-4 minutes. Gentle inflation of the lung may assist this process. When back-bleeding occurs or after several minutes if no back-bleeding results, the pulmonary artery clamp is gradually removed as the pulmonary artery suture is tied. The bronchial suture line is tested for air leaks, and the omentum is withdrawn from its position in the anterior mediastinum, is brought inferior and posterior to the hilum of the lung, and is completely wrapped around the bronchus (Fig 16). DOUBLE

LUNG

TRANSPLANT

OPERATION

The double lung procedure requires total cardiopulmonary bypass with a period of aortic crossclamping and myocardial protection. The single lumen endotracheal tube is used. Induction of anes724

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Probl

Sur5

October

1989

thesia and positive pressure ventilation in patients with severe obstructive lung disease may precipitate a marked fall in cardiac output caused by gas trapping in the lungs. Cardiopulmonary bypass should therefore be available before induction of anesthesia. Very gentle, manual inflation should be done initially before attaching the patient to a positive pressure ventilator. We occasionally find it necessary to use a high-frequency jet ventilator. Because of the significant risk of bleeding during the extraction of the diseased lungs, we have employed a “low-dose” heparin protocol, 1.5 to 2 mg/kg initially, to maintain an activated clotting time of 250 to 400 seconds. This is based upon our experience with longterm extracorporeal membrane oxygenation47 and recent animal data.“” We believe that the reduced dose of heparin combined with core cooling provides adequate anticoagulation but with reduced intraoperative and postoperative bleeding. Surgical Technique With the patient in the supine position the chest and abdomen are prepared. The groins are draped to allow for rapid institution of bypass should this be necessary after intubation and ventilation. Median sternotomy is performed and is extended inferiorly as an upper abdominal midline incision. The omentum is mobilized as for single lung transplant. The pericardium is opened, and the proximal aorta, common pulmonary artery, and both venae cavae are isolated and loosely encircled with umbilical tape (Fig 17). To reduce bleeding, as much of the subsequent dissection as possible is performed before heparinization. Dissection should be carried out using electrocautery as much as possible. The proximal left pulmonary artery is isolated. The right pulmonary artery is isolated between the aorta and the vena cava. The pleural spaces are entered, and pleural adhesions are taken down using cautery. Cardiopulmonary bypass is instituted using double caval cannulation and standard ascending aortic cannulation. In addition, a right ventricular vent is placed through a small right atria1 pursestring suture. After institution of cardiopulmonary bypass, the heart remains empty but beating as the core temperature is lowered to 32’ C. The left pulmonary veins are stapled close to the heart and divided. The left pulmonary artery is stapled just inside the pericardium and divided (Fig 18). The left main bronchus is divided between staple lines to avoid contamination of the pleural space. After excision of the left lung, a pleuropericardial window is created posterior to the left phrenic nerve by enlarging the pericardial opening through which the pulmonary veins exit (Fig 19). The right lung is then excised in similar fashion. The pulmonary artery is stapled in the mediastinum where previously mobilized Curr

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Sur5

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1989

725

FIG 17. The omentum is mobilized after extending the sternotomy laparotomy. The great vessels are surrounded with umblkal

incision tapes,

inferiorly

to a midllne

and then divided outside the pericardium. The pulmonary veins are stapled within the pericardium and divided. The right main bronchus is divided between staple lines, and the right lung is removed. A pleuropericardial window is created on the right side posterior to the phrenic nerve, from the level of the diaphragm to the level of the azygous vein, which is also divided to further enlarge the window (Fig 20). The stumps of the right and left main bronchi are then carefully dissected free. This is done most easily through a right-sided approach, though it can be done through the mediastinum as well. Extreme care must be taken to coagulate or ligate bronchial arteries to avoid subsequent hemorrhage from the posterior mediastinum. The previously mobilized omentum is passed through a fenestration created in the midportion of the diaphragm, behind the heart and into the superior mediastinum. The heart is elevated, the double lung bloc is passed behind, and each lung is directed through its respective pleuropericardial window into its pleural space. The trachea is withdrawn into the superior mediastinum. This is facilitated by leaving an umbilical tape sutured to the stump of the donor trachea and guiding the block into place by traction on the tape. The first connection is an end-to-end tracheal anastomosis. The recipient trachea is transected just above the carina, and the bron726

Curr

Probl

Surg,

October

1989

FIG 18. Technique of left pneumonectomy for double doubly stapled and dlvlded Intrapericardially. stapled and divided intrapericardially.

lung transplant. The left pulmonary veins are The left pulmonary artery is likewise doubly

chial stumps and carina are discarded. The donor trachea is transected two rings above the carina. The membranous wall is sutured using a running monofilament absorbable suture. The cartilaginous portion of the tracheal anastomosis is performed with interrupted absorbable suture (Fig 21). Upon completion of the airway anastomosis, the omentum is wrapped completely around the suture line. Once the lung bloc is in place the aorta is crossclamped and the heart is arrested with cold potassium cardioplegia. The heart is retracted upward and to the right, and an opening is made in the recipient left atrium by excising the left pulmonary venous stumps and carrying the incision onto the back wall of the left atrium (Fig 22). The donor atrial cuff is then anastomosed. The cross clamp is removed after completion of the left atrial anastomosis. The heart is returned to its normal position, and the recipient pulmonary artery is transected just proximal to its bifurcation. The donor and recipient pulmonary arteries are then anastomosed in an end-to-end fashion, completing the procedure. Despite the demonstration that omentopexy can revascularize the trachea (Fig 231, tracheal healing has been a problem after double Corr

Probl

SW&

October

1989

727

FIG 19. A left pleuropericardial where the pulmonary

window is fashioned posterior veins exit the pericardium

to the

left phrenic

nerve

at the site

lung transplantation. Accordingly, we and other groups have recently begun to use bilateral bronchial anastomoses rather than tracheal anastomosis. Noiclerc and colleagues in Marseilles’30 recently reported excellent results in a series of patients in whom this technique was used. We, too, have been pleased with our initial experience using this technique. There is evidence that in dogs the pulmonary circulation contributes to the blood supply of the main bronchi, but the contribution to the distal trachea is considerably less. I’, lzo This may help explain the observed higher incidence of airway complications after double as compared with single lung transplant. In addition we are evaluating a technique for direct bronchial artery revascularization after single lung and double lung transplantation by preserving a donor bronchial artery with a patch of aorta to be reimplanted into the recipient aorta (Fig 241.167 POSTOPERATIVE COURSE TRANSPLANTATION

FOLLOWING

LUNG

The first hours after surgery may be marked by a high arterial-alveolar (Aa) gradient. We reviewed the early Aa gradient as a function of donor ischemic time after transplantation and found no relation728

CurrProblSurg,

October

1989

FIG 20. On the right side the pleuropericardial nerve In the area of exit of the right large this pleuropericardial window.

window pulmonary

IS created veins. The

posterior azygous

to the right phr%nic vein is divided to en-

ship between Aa gradient and duration of donor lung ischemia. The results are shown graphically in Figure 2.5. The transplanted lung is susceptible to fluid overload, perhaps because of the total disruption of pulmonary lymphatics combined with the increase in extravascular lung water that accompanies reimplantation.31 We employ lowdose pressor support rather than volume infusion once adequate filling pressures have been established. Transcutaneous oximetry, arterial pressure, and pulmonary artery pressures are continuously monitored. Cardiac output and mixed venous saturation is measured at appropriate intervals. lntraoperative and postoperative hemorrhage has been a problem in some double lung transplant recipients, especially those with inflammatory disease such as cystic fibrosis or bronchiectasis. We suspect that prolonged postoperative hemorrhage and hypotension may contribute significantly to subsequent fatal ischemic airway problems. Patients are weaned from ventilatory support as early as possible. We feel that this is facilitated by the preoperative rehabilitation program. Clearly, the longer intubation is required, the higher the likelihood of pneumonia developing. This is of particular concern in paCum

Probl

Surg

October

1989

729

FIG 21. Technique of tracheal anastomosis. Upper left, the posterior membranous wall is sutured with running monofilament suture. Excess donor trachea (2 rings above carina) is discarded. Upper right, the front wall is completed with interrupted absorbable suture. Lower right, after completion of the airway anastomosis, the omentum is used to wrap the anastomosis.

tients with infective end-stage lung disease whose upper and lower airways are colonized at the time of transplantation. We monitor the airway with frequent bronchoscopies, usually performing the initial one on the first postoperative day. It is important to assess the airway anastomosis and to obtain appropriate cultures if indicated. We utilize bronchial washings, BAL, and protected brush specimens with quantitative culture techniques.25’ g3*lgo Bronchoscopy is performed before extubation and again 2 to 3 weeks later to assess airway healing before adding maintenance prednisone to the immunosuppressive regimen. As with other surgical procedures on the airway, ischemic injury may not be apparent until the third postoperative week. Anecdotally, we have noticed that many patients have a prolonged ileus after lung transplantation, out of proportion to what might be anticipated after omental mobilization. Whatever the cause, the end result is that the gut is often not useful as a route of alimentation in these patients, and gastric distention necessitates nasogastric tube suction for a prolonged period postoperatively. This prolonged ileus 730

Cur-r

Probl

Sur5

October

1989

FIG 22. Excision of the left pulmonary vein stumps, with extension of this atriotomy duces a window into the left atrium for anastomosis of the donor left atrial

to the right cuff.

pro-

frequently mandates the use of postoperative intravenous total parenteral nutrition. Patients walk as early as possible, using supplemental oxygen as necessary and monitoring transcutaneous oxygen saturation. Vigorous chest physiotherapy is essential for optimal mobilization of secretions. Our immunosuppression protocol consists at the outset of cyclosporine (4 mghr), azathioprine (2 mgkgday), and antilymphocyte globulin (15 mgkgday), all given intravenously. We start the intravenous cyclosporine at the conclusion of the transplant operation. Therapy is monitored with whole blood radioimmunoassay using a monoclonal antibody technique. We attempt to achieve a blood level in the range of 300 to 400 rig/ml during intravenous therapy. When the gastrointestinal tract appears to be functioning, oral cyclosporine is administered and is adjusted to provide trough levels in this range. We avoid routine daily use of steroids for the first 3 weeks because of the deleterious effect on bronchial wound healing. Suspected immunologic rejection is treated with bolus doses of steroids although the diagnosis of rejection is difficult. Early acute rejection has been an almost constant feature of isolated lung transplantation with 2 or 3 rejection episodes usually occurring within the first month. These episodes are well managed with pulsed steCum

Probl

Sur5

October

1989

731

FIG 23. Angiogram made by injection of contrast material Into who had died 6 weeks after double lung transplant. crsed from the specimen except for a small button at main stem bronchus that was densely adherent to opacrfrcation of multiple small vessels in the donor omentum was able to revascularize the transplanted

the gastroepiplorc artery of Most of the omentum has the Juncture of the trachea the outside of the arrway. airway (arrows) confrrming tissue.

a patient been exand right Note the that the

roid therapy. Clinical signs include a temperature elevation that may be as slight as 0.5” C, a deterioration in gas exchange as seen by a decrease in PO,, or a decrease in exercise tolerance. Radiographically the appearance of a fluffy hilar infiltrate is quite suggestive of immunologic rejection, especially if it occurs during days 4-6 following transplantation. However, we recognize that these same changes may be seen with infection, and as previously noted, bronchoscopy is helpful to rule out infection. We consider radiographic changes to be late signs of rejection, and thus we maintain a low threshold for giving an initial bolus of steroid (500 mg methylprednisolone sodium succinate). The diagnosis of immunologic rejection is frequently confirmed by virtue of the response to a bolus dose of steroids. Significant resolution of the infiltrate is usually seen within 12 hours of the first dose of steroid. If there has been a clear-cut clinical or radiologic response to the initial steroid bolus, it is followed by two subsequent doses of steroids on the succeeding 2 days (250 to 500 mg of methylprednisolone sodium succinate). 732

Cum

Pro61

Surg,

October

1989

FIG 24. Systemic blood supply to the arrway (A) demonstrated by rnfectron of the rrght intercostal bronchial artery of an autopsy specimen. We have developed a technrque to harvest this pedrcle (B) in an attempt to improve airway blood supply after double lung transplantatron. (From Schreinemakers HJ, Weder W, Mryoshi S, et al Direct revascularization of bronchial arteries for lung transplantation. Ann Thorac Surg, submitted for publication.)

In single lung recipients, immunologic rejection is usually accompanied by a reduction in perfusion to the transplanted lung documented on quantitative radionuclide scan to determine the percentage of total blood flow to each lung. Despite the sensitivity of this technique, it is not necessarily specific. This perfusion redistribution is promptly reversed with a pulse dose of steroids. With few exceptions a rejection episode occurs during the first 5 to 6 days after transplant. This corresponds to classical first set immunologic rejection and is the same time frame in which rejection develops in untreated laboratory animals after a lung allograft.‘“‘, 2’S A second rejection episode between 2 and 3 weeks postoperatively is also a frequent occurrence. Because of the frequency of immunologic rejection episodes despite “triple therapy” we have recently begun to explore the use of the murine monoclonal antibody OKT-3 for initial prophylaxis, an agent for which there is favorable experience in cardiac transplant patients.“’ Is4 After the first month following successful transplantation, immunologic rejection is unusual. However, two of our recipients have died from what appeared to be chronic rejection. Curr

Probl

Surg,

October

1989

733

350 0 Single Lung TX - 0 Double Lung TX

300

AaDO

*O”

(torr)

,50

l

0l 0

0 .

0

0

8

0

00

0

0

0

0

50

100 lschemic

150

200

250

300

Time (min)

FIG 25. Scattergram of postoperative Aa gradient vs. ischemic time for 23 lung transplants. Using simple atelectasis and cold immersion as a method of preservation, there was no apparent relationship between ischemic time and early lung function as assessed by Aa gradient

Experience with airway complications after lung transplantation airhas been recently reviewed.‘36’ I” Of 17 single lung transplants, way necrosis caused 1 death. This was the only patient receiving a transplant while still on steroids. Two patients required insertion of Silastic stents for anastomotic stenoses, a technique previously described”’ (Pig 26). One of these patients subsequently died from chronic rejection, and the other remains alive and well nearly 5 years after transplantation. Of 16 double lung recipients in our experience, 3 died in the perioperative period, leaving 13 patients at risk for airway complications. Of these, 3 patients died of complications directly related to airway necrosis or dehiscence, and 2 additional patients have had placement of silicone elastomer (Silastic) airway stents (Fig 27). Infectious complications after lung transplantation have also recently been reviewed (H. Vellend, personal communication, April 1989). Of the first 30 single or double lung transplants performed by the Toronto Lung Transplant Group, 32 infections occurred in 19 patients, most within 6 months of transplantation. Twenty of 32 infections involved the chest. Seven patients who were seronegative for cytomegalovirus (CMV) received seropositive lungs. Two of these patients seroconverted but had no evidence of clinical infection. The 734

Corr

Probl

SW-~, October

1989

FIG 26. These intralumlnal scoplcally.

airway

stents

are

fashioned

from

Sllastic

and

can

be

inserted

endo-

only patient in whom fatal CMV pneumonia developed was seropositive and received a seronegative graft. We routinely employ Pneumocystis prophylaxis with trimethoprim and sulfamethoxazole as well as herpes prophylaxis with acyclovir. CLINICAL

RESULTS

OF LUNG

TRANSPLANTATION

A report detailing results in our first 11 single lung transplant recipients has been published.lSg The experience of one of the authors (JDC) includes 17 single lung transplants performed since 1983 with an absolute survival rate of 65% and the longest survivor at 5.5 years. The majorityofpostoperative deaths resulted from poordonor selection, an area in which we have subsequently made significant improvements. We recently established a Registry of Lung Transplantation, and as of April 1989 we have reports of 76 single lung transplants performed worldwide since 1983, with 46 (60%) of all recipients being alive and well. Our initial experience with double lung transplantation has also been reported.” One of the authors’ (JDC) personal experience involves 14 recipients, with 9 (65% 1 long-term survivors, including 4 patients alive at 2 years or longer and 1 cystic fibrosis patient alive 14 months after transplantation. Fatal airway complications occurred Curr

Probl

Surg,

October

1989

735

FIG 27. Computed tomographic scan showing a SIlastIc stent In the left main stem bronchus of a double lung transplant recipient. (From Cooper JD, Pearson FG, Patterson GA, et al: Use of silicone stents in the management of alrway problems. Ann Thorac Surg 1989; 47:371-378. Used by permission.)

in 3 patients, and late airway stenosis developed in an additional 3 patients requiring dilatation or Silastic stent insertion or both. Data from the Lung Transplant Registry shows 49 double lung transplants with overall long-term survival of 57%. After successful single lung transplantation, there is a progressive increase in blood flow to the transplanted lung as documented by serial perfusion lung scans5’ In our experience the mean perfusion to the transplanted lung is 66% at 1 week, 72% at 3 weeks, with subsequent gradual increase.ls9 In some cases where there is increased pulmonary vascular resistance in the native lung, perfusion to the transplanted lung has been more than 80% in the first 24 hours. Improvements in ventilation and lung function for single and double lung recipients are shown in Figures 28 and 29. The improvement in measured volumes is accompanied by a marked increase in exercise capacity in these patients (Figures 30 and 311 .53z54 Improvement in lung function and exercise capacity have been sustained in all of our isolated lung transplant patients with the exception of the two patients in whom chronic immunologic rejection developed. To date, no patient has had reinnervation of a transplanted lung, 736

Cur-r Probl

SW-~, October

1989

A

aor

TomI Lung Capawy aller Smgle Lung Transplantal~,n

V~lalCapacdy afkr Smgle Lung Transplan~a~,on

DC0 alkr Single Lung Tran~plantalm

FIG 28. Improvements in total lung capacity (A) FEV, (B), vital capacity (C), and diffusing capacity for carbon monoxide (D) after single lung transplantation (From Frost A, Maurer JR, Zamel N, et al: Improvement in pulmonary function, graft perfusion, and exercise tolerance following single lung transplantation for pulmonary fibrosis. Submitted for publication.)

as determined by the absence of cough upon stimulation of the transplanted airway at the time of bronchoscopy. There is evidence that autonomic reinnervation may occur in dogs after pulmonary reimplantation.45’ lo5 Higenbottam and colleagues showed that in humans the pattern of breathing after heart-lung transplantation is normal during rest and exercise despite pulmonary denervation.8” Carbon dioxide response curves and sleep studies have been done in patients after single lung, double lung, and combined heart-lung transplantation and have been found to be normal. We have demonstrated airway hyperreactivity in patients undergoing single lung and combined heart-lung transplantation, suggesting Cur-r

Probl

SW..

October

1989

737

FEV, (LitreM Sacondl

P0stop

Preop

Preop

Postop

C DLCO (ml/mid mmHgl

I Preop

Postop

FIG 29. Improvement in FEV, (A), total lung capcity (6) and diffusing capacity ide (C) following double lung transplantation in the first six double formed by the Toronto Lung Transplant Group.

for carbon monoxlung recipients per-

that denervation may play a role in airway hyperresponsiveness in manIl Increased airway hyperreactivity in the denervated lung has also been reported by others after combined heart-lung transplant.“’ We measured mucociliary clearance and ciliary beat frequency in five patients, 6 to 12 months after single lung transplantation for pulmonary fibrosis.42 Mucociliary clearance was measured over 6 hours by monitoring the disappearance of an inhaled ssmTc-sulfur colloid aerosol. The clearance rate of the aerosol from the transplanted lung was less than 50% of that in the opposite, native lung. Bronchial biopsy specimens were taken from both native and transplanted lungs to measure ciliary beat frequency using phase contrast light microscopy. In all specimens ciliary activity appeared normal. We concluded that the abnormality in mucociliary clearance was unrelated to ciliary beat frequency but might reflect a quantitative or qualitative defect in mucous or periciliary fluid composition after transplantation. Edmunds also demonstrated impaired mucociliary clearance using tantalum bronchography in a canine lung transplant mode1.46 738

Curr

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1989

We did not anticipate that the double lung transplant procedure would affect cardiac innervation, but recent studies show a variable degree of denervation after this procedure.*” Evaluation of maximal heart rate after carotid sinus massage, Valsalva maneuver, and intravenous atropine, and during the first 3 minutes of rest after a standardized exercise test was performed in four double lung recipients and revealed a normal response in two patients. However, the other two patients had minimal response, indicating at least some degree of cardiac denervation. To date, recurrence of the original lung disease for which patients received a single lung, double lung, or heart-lung transplant has not been observed. This includes patients transplanted for idiopathic pulmonary fibrosis, cystic fibrosis, and primary pulmonary hypertension.

800

700 F 600 t

B 500Y 5 z 3004Gil-

2

200

n

lOO-

01’ pre-op

3 6 9 1 Months after Transplantation

12

FIG 30. Improvement in exercise performance as assessed by meters walked In 6 minutes following single lung transplantatlon. (From Frost A, Maurer JR, Zamel N, et al: Improvement tn pulmonary function, graft perfusion, and exercise tolerance following single lung transplantation for pulmonary fibrosis. Submitted for publication.)

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Metredmin.

100

-

90

-

80

-

70

-

60

-

50

-

40,

fl=8 -l-

OL

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I Months

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9

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after Transplantation

FIG 31. Improved performance In 6-minute walk after double lung transplantation. (From Frost A, Dear CL, Grossman RF, et al: Exercise tolerance In patients undergolng double lung transplant for end stage pulmonary disease. Am Rev Respir D/s 1988; 137:336 [abstract]. Used by permIssIon.)

SUMMARY

AND

CONCLUSIONS

The supply of donor organs remains extremely limited, and improved methods of maintaining the lungs of potential donors to allow for transplantation must be developed. Currently the upper limit of donor lung ischemic even with our “best” preservation techniyues is approximately 4 to 6 hours. Improved methods for preservation will increase the supply of suitable lungs and will considerably simplify the logistics of transplantation just as has occurred with liver transplantation. Efficient use of donor organs remains of paramount importance. We recently performed two single-lung transplants utilizing lungs from one donor. Likewise, there is no reason why a lung could not be sent to another center for transplantation if the harvesting group uses only one lung. Sufficient progress has been achieved to date to warrant continued application of lung transplantation for end-stage pulmonary disease. With increasing experience, one can anticipate refinement of techniques and broader application of these procedures. Single lung transplantation, initially restricted to patients with end-stage pulmonary fibrosis, has now been successfully applied to patients with emphysema, pulmonary hypertension, and other conditions. 740

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Although transplantation currently can offer real benefit only to a limited number of persons, it serves to create hope for many others. An additional benefit may prove to be the interest and attention that transplantation focuses on patients with end-stage lung disease and on the pathophysiologv of chronic respiratory failure. Knowledge gained may ultimately result in the prevention of many of the disorders for which lung transplantation currently offers the only hope. ACKNOWLEDGMENTS

The authors wish to acknowledge the expert assistance of Kathy Jones and Mary Ann Kelly in preparation of this manuscript. We also wish to acknowledge the enthusiastic support receved from many members of the medical nursing and physiotherapy staffs at the University of Toronto and Washington University, whose combined efforts made transplantation for end-stage lung disease a reality. REFERENCES

1. Ackerman DM, Edwards WD: Sudden death as the initial manifestation of primary pulmonary hVypertension. Am J Forensic Med Pathol 1987; 8:97-102. 2. Adachi H, Fraser CD, Kontos GJ, et al: Autoperfused working heart-lung preparation versus hypothermic cardiopulmonary preservation for transplantation. J Heart Transplant 1987; ti:253-260. 3. Alican F, Cayirli M, Isin E, et al: Feasibility of simultaneous bilateral lung replantation. Transplant Proc 1971; 3524-526. 4. Alican F, Hardy JD: Lung reimplantation. JAMA 1963; 183:849-853. 5. Allen MD, Burke CM, McGregor CGA, et al: Steroid-responsive bronchiolitis after human heart lung transplantation. J Thorac Cardiovasc Surg 1986; 92:449-4.51. 6. Allgood RI, Ebert PA, Sabiston DC: Immediate changes in pulmonary hemodynamics following lung autotransplantation. Ann Surg 1968; 167: 352- 358. 7. Andrews MJ, Pearson FG: Relation to bronchial arterial circulation, and other factors, to the transient defect in oxygen uptake following autotransplantation of the canine lung. Can J Surg 1973; 16:97-109. 8. Arumugan S, Nimmannit S, Enquist IF: The effect of immunosuppression on wound healing. Surg Gynecol Obstet 1971; 133:72- 74. 9. Baldwin JC, Oyer PE, Stinson EB, et al: Comparison of cardiac rejection in heart and heart-lung transplantation. J Heart Transplant 1987; 6:352-356. 10. Bando K, Tago M, Teraoka H, et al: Extended cardiopulmonary preservation for heart-lung transplantation: A comparative study of superoxide dismutase. J Heart Transplant 1989; 8:59-66. 11. Barman SA, Ardell JL, Parker JC, et al: Pulmonary and systemic blood flow contributions to upper aitways in canine lung. Am J Physiol 1988; (Heart Circ Physiol 24) 255:H1130-H1135. 12. Barnhard CN: A human cardiac transplant. S Afr &fed J 1967; 41:1271-1274. 13. Bart KJ, Macon EJ, Humphries AL, et al: Increasing the supply of cadaveric kidneys for transplantation. Transplantation 1981; 31:383-387. Curr

Probl

Surg

October

1989

741

14. Benfield JR, Coon R: The role of the left atria1 anastomosis in pulmonary replantation. J Thorac Cardiovasc Surg 1967; 53:676-684. 15. Blumenstock DA, Grosjean OV, Otte HP, et al: Experimental aflotransplantation of the lung. J Thorac Cardiovasc Surg 1967; 54:807-814. 16. Bogardus GM: Evaluation in dogs of the relationship of pulmonary, bronchial, and hilar adventitial circulation to the problem of lung transplantation. Surgery 1958; 43:849-856. 17. Boychuk JE, Patterson GA: Assessing heart and lung donors, Diagnosis 1988; 5:165-173. 18. Breda MA, Hall TS, Stuart RS, et al: Twenty-four hour lung preservation by hypothermia and leukocyte depletion. Heart Transplant 1985; 4:325-329. 19. Bristow MR, Gilbert EM, Renlund DG, et al: Use of OKT3 monoclonal antibody in heart transplantation: Review of the initial experience. J Heart Transplant 1987;7:1-11. 20. Bryan CL, Cohen DJ, Dew A, et al: Glutathione decreases the pulmonary reimplantation response in canine lung autotransplants. Am Rev Resp Dis 1989; 139A45 (abstract). 21. Burke CM, Morris AJR, Dawkins KD, et al: Late airflow obstruction in heartlung transplantation recipients. Heart Transplant 1985; 4:437-440. 22. Byers JM, Sabanayagam P, Baker RR, et al: Pathologic changes in baboon lung allografts. Ann Surg 1973; 178:754-760. 23. Cardosa PFG, Yamazaki F, Keshavjee S, et al: Reevaluation of heparin requirements for safe cardiopulmonary bypass. J Thorac Cardiovasc Surg, in press. 24. Carrel A: The surgery of blood vessels, etc. Bull Hopkins Hosp 1907; 18:18-28. 24a. Carrel A: Anastomosis of blood vessels by the patching method and transplantation of the kidney. JAMA 1908; 51:1658-1661. 25. Chastre J, Fagon JY, Soler P, et al: Diagnosis of nosocomial bacterial pnuemonia in intubated patients undergoing ventilation: Comparison of the usefulness of bronchoalveolar lavage and the protected specimen brush. Am J Med 1988;85:499-506. 26. Christiansen KH, Smith DE, Pinch LW: Homologous transplantation of canine lungs: Technique with contralateral pulmonary artery ligation. Arch Surg 1963;86:495-499. 27. Collins GM, Bravo-Shugarman M, Terasaki Pi: Kidney presevation for transportation: Initial perfusion and 30 hours ice storage. Lancet 1969; 2:1219-1222. 28. Cooper JD, Patterson GA, Grossman R, et al: Double-lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989; 139:303-307. 29. Cooper JD, Pearson FG, Patterson GA, et al: Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 1987; 93:173-181. 30. Cooper JD, Pearson FG, Patterson GA, et al: Use of silicone stems in the management of ain/vay problems. Ann Thorac Surg 1989; 47:371-378. 31. Cowan GS, Staub NC, Edmunds LH: Changes in the fluid compartments and dry weights of reimplanted dog lungs. J AppZ Physiol 1976; 40:962-970. 32. Crane R, Torres M, Hagstrom JWC, et al: Twenty-four hour preservation and transplantation of the lung without functional impairment. Surg Forum 1975;26:111-113. 33. Daicoff GR, ANen PD, Streck CJ: Pulmonary vascular resistance following lung reimplantation and transplantation. Ann Thorac Surg 1970; 9:569- 579. 34. Dal Co1 RH, Rabinovich H, Herlan DB, et al: Donor specific cytotoxicity test742

Cum

Rmbl Surf Dctober

1989

35. 36. 37. 38.

39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. Cur-r

ing: An advance in detecting pulmonary allograft rejection. Ann Thorac Surg, in press. Daily PO, Dembitsky WP, Peterson KL, et at: Modifications of techniques and early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. J Thorac Cardiovasc Surg 1987; 93:221-233. Daniel RA: The regeneration of defects of the trachea and bronchi: An experimental study. J Thorac Surg 1948; 17:335-349. Dark JH, Patterson GA, Al-Jilaihawi AN, et al: Experimental en bloc doublelung transplantation. Ann Thorac Surg 1986; 42:394-398. DeMajo WAP: Anaesthetic technique for single lung transplantation, in Cooper DKC, Novitzky D teds): The Transplantation and Replacement oj Thoracic Organs. Lancaster, England, Kluwer Academic Publishers, in press. Demikhov VP: E,xperimental Transplantation qf Vital Organs. New York, Consultants Bureau Enterprises, 1962. Demling RH: Role of prostaglandins in acute pulmonary microvascular injury. Ann NY Acad Sci 1982; 384:517-534. Derom F, Barbier F, Ringoir S, et al: Ten month survival after lung homotransplantation in man. J Thorac Cardiovasc Surg 1971; 61:835846. Dolovich M, Rossman C, Chambers C, et at: Muco-ciliary function in patients following single lung or lung/heart transplantation. Am Rev Respir Dis 1987; 135A363 (abstract). Drews JA, Tierney DF, Benfield JR: Effect of lung transplantation on surfactant. Surg Forum 1973; 24:334-336. Dubois P, Choiniere L, Cooper JD: Bronchial omentopexy in canine lung allotransplantation. Ann Thorac Surg 1984; 38:211-214. Edmunds LH, Graf PD, Nadel JA: Reinnervation of the reimplanted canine lung. J Appl Physiol 1971; 31:722-727. Edmunds LH, Stallone RJ, Graf PD, et al: Mucus transport in transplanted lungs of dogs. Surgery 1969; 66:15-Z. Egan TM, Duffin J, Glynn MFX, et al: Ten-year experience with extracorporeal membrane oxygenation for severe respiratory failure. Chest 1988; 94:681- 693. Egan TM, Saunders NR, Dubois P, et al: Contribution of circulating formed elements to prostanoid production in complement-mediated lung injury in sheep. Surgery 1985; 98:350-357. Eloesser L: Transthoracic bronchotomy for removal of benign tumours of the bronchi. Ann Surg 1940; 112:1067-1070. Eraslan S, Turner MD, Hardy JD: Lymphatic regeneration following lung reimplantation in dogs. Surgery 1964; 56:970-973. Faber LP, Kenwell JM, Beattie EJ: Homologous lung transplantation: Experience in the dog. Arch Surg 1961; 83:491-495. Fisher AB, Kollmeier H, Brady JS, et al: Restoration of systemic blood Row to the lung after division of bronchial arteries. J Appl Physiol 1970; 29:839-846. Frost A, Dear CL, Grossman RF, et al: Exercise tolerance in patients undergoing double lung transplant for end stage pulmonary disease. Am Rev Respir Dis 1988; 137:336 (abstract). Frost A, Maurer JR, Zamel N, et al: Improvement in pulmonary function, graft perfusion, and exercise tolerance following single lung transplantation for pulmonary fibrosis. Submitted for publication. Fujimura S, Handa M, Kondo T, et al: Successful 48hour simple hypotherl’robl

SW-

October 1989

743

56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.

744

mic preservation of canine lung transplants. Transplant Prflc 1987; 19:1334- 1336. Fujimara S, Rosen V, Adomian GE, et al: Cellular characteristics of the rejection response to canine lung allotransplants. J Thorac Cardiovasc Surg 1973; 65:438-448. Fuster V, Steele PM, Edwards WD, et al: Primaly pulmonary hypertension: Natural history and the importance of thrombosis. &culation 1984; 70:580-585. Gadek JE, Fells GA, Zimmerman RL, et al: Antielastases of the human alveolar structures: Implications for the protease-antiprotease theory of emphysema. J Clin Invest 1981; 68:889-898. Garzon AA, Cheng C, Pangan J, et al: Hypothermic hyperbaric lung preservation for twenty-four hours with replantation. J Thorac Cardiovasc Surg 1968; 55:546-554. Gebauer PW: Plastic reconstruction of tuberculous bronchostenosis with dermal grafts. J Thorac Surg 1950; 19:604-628. Glanville AR, Burke CM, Theodore J, et al: Bronchial hyper-responsiveness after human cardiopulmonary transplantation. Clin Sci 1987; 73:299-303. Glanville AR, Burke CM, Theodore J, et al: Primaty pulmonary hypertension: Length of survival in patients referred for heart lung transplantation. Chest 1987; 91:675-681. Goldberg M, Lima 0, Morgan E, et al: A comparison between cyclosporin A and methylprednisolone plus azathioprine on bronchial healing following canine lung autotransplantation. J Thorac Cardiovasc Surg 1983; 85:821-826. Goldsmith JS, Kiely AA, Randal HT: Protection of intrathoracic esophageal anastomoses by omentum. Surgery 1968; 63:464-466. Gondos B, White P, Benfield JR: Histologic changes associated with rejection of canine lung transplants. J Thorac Cardiovasc Surg 1971; 62:183-187. Griffith BP: Detection of rejection in the transplanted lungs and immunology, in Wallwork J (ed): Heart and Heart-Lung Transplantation. Philadelphia, WB Saunders Co, 1989, pp 507-521. Griffith BP, Paradis IL, Zeevi A, et al: Immunologically mediated disease of the airways after pulmonary transplantation. Ann Surg 1988; 208:371-378. Grosjean 0, Leroux G, Schepens-Rocoux G, et al: Double lung transplantation through right thoracotomy and without extracorporeal circulation. Acta Chir Belg 1976; 75:427-434. Gryzan S, Paradis I, Griffith BP, et al: T-lymphocyte subset recovery by bronchoalveolar lavage during infection and rejection of the transplanted lung. Heart Transplant 1985; 4:611 (abstract). Gryzan S, Paradis IL, Hardesty RL, et al: Bronchoalveolar lavage in heartlung transplantation. Heart Transplant 1985; 4:414-416. Hachida M, Morton DL: The protection of ischemic lung with verapamil and hydralazine. J Thorac Cardiovasc Surg 1988; 95:178-183. Haglin JJ, Arnar 0: Physiologic studies of the baboon living on only the reimplanted lung. Surg Forum 1964; 15:175-176. Hall TS, Borkon AM, Gurtner GC, et al: Improved static lung preservation with corticosteroids and hypothermia. J Heart Transplant 1988; 7:348-352. Hardin CA, Kittle CF: Experiences with transplantation of the lung. Science 1954; 119:97-98. Hardy JD, Alican F: Lung transplantation. Adv Surg 1966; 2:235-264. Hardy JD, Eraslan S, Dalton ML: Autotransplantation and homotransplantation of the lung: Further studies. J Thorac Cardiovasc Surg 1963; 46:606-615. Cur-r

Probl

SW-~,

October 1989

77. Hardy JD, Eraslan S, Dalton ML, et al: Reimplantation and homotransplantation of the lung. Ann Surg 1963; 157:707. 78. Hardy JD, Webb WR, Dalton ML, et al: Lung homotransplantation in man. JAMA 1963; 186:1065-1074. 79. Haverich A, Scott WC, Jamieson SW: Twenty years of lung preservation: A review. Heart Transplant 1985; 41234-240. 80. Haworth SG: Primary pulmonary hypertension. Br Heart J 1983; 49:517-521. 81. Herlan D, Kormos R, Zeevi A, et al: Dynamics of bronchoalveolar lavage in the canine lung transplant. Transplant Proc 1988; ZO(supp1 1):832-835. 8.2. Higenbottam T: Physiology of the transplanted lung and the results, in Wallwork J ted): Heart and Heart-Lung Transplantation. Phildelphia, WB Saunders Co, 1989, pp 533-544. 83. Higenbottam T, Hutter JA, Stewart S, et al: Transbronchial biopsy has eliminated the need for endomyocardial biopsy in heart-lung recipients. J Heart Transplant 1988; 7:435-439. 84. Higenbottam T, Stewart S, Wallwork J: ‘Transbronchial lung biopsy to diagnose lung rejection and infection of heart-lung transplants. Transplant Proc 1988; 2OtSuppl 1):767-769. 85. Higgins M: Epidemiology of COPD: State of the art. Chest 1984; 85 (supplI:3S-8s. 86. Hoyer J, Garbe L, Delpierre S, et al: Functional evaluation of the transplanted lung after long-term preservation. Respiration 1980; 39:323-332. 87. Hsieh CM, Mishkel G, Rakowski H, et al: Production and reversibility of right ventricular hypertrophy and right ventricular failure in dogs. Submitted for publication. 88. Hutchison DCS: Natural history of alpha-l-protease inhibitor deficiency. Am J Med 1988; 841Suppl 6A):3-12. 89. Jones MT, Hsieh C, Yoshikawa K, et al: A new model for assessment of lung preservation. J Thorac Cardiovasc Surg 1988; 96:608-614. 90. Joseph WL, Morton DL: Long term survival in the immediately functioning transplanted primate lung. Ann Thorac Surg 1971; 11:442-449. 91. Jurman MJ, Dammenhayn L, Schafers HJ, et al: Prostacyclin as an additive to single crystalloid flush: Improved pulmonary preservation in heart-lung transplanation. Transplant Proc 1987; 19:4103-4104. 92. Juvenelle AA, Citret C, Wiles CE, et al: Pneumonectomy with replantation of the lung in the dog for physiologic study. J Thorac Surg 1951; 21:111-113. 93. Kahn FW, Jones JM: Diagnosing bacterial respiratory infection by bronchoalveolar lavage. J Infect Dis 1987; 155:862-869. 94. Kamholz SL, Veith FJ, Mollenkopf RP, et al: Single lung transplantation with cyclosporin immunosuppression. 3 ‘t’horac Cardiovasc Surg 1983; 86: 537-542. 95. Karlson KE, Garzon AA, Goldstein S, et al: Functional evaluation of immediately replanted and 24 hour preserved and replanted lungs after longer than one year. Bull Sot Int Chirurg 1970; 3:175-181. 96. Keon WJ, Hendry PJ, Taichman GC, et at: Cardiac transplantation: The ideal myocardial temperature for graft transport. Ann Thorac Surg 1988; 46:337-341. 97. Kern JA, Fishman AP: End stage fibrotic lung disease: Treatment and prognosis, in Fishman AP (edI: Pulmonary Diseases and Disorders. New York, McGraw Hill, 1988, pp 2237-2250. 98. Keshavjee SH, Yamazaki F, Cardoso PF, et al: A method for safe 12 hour pulmonary preservation. J Thorac Cardiovasc Surg, in press. Curr

Probl

Surg,

October

1989

745

99. Kirby JA, Parfett GJ, Reader JA, et al: Lung transplantation in the rat: A model for the study of the cellular mechanisms of allograft rejection. Immunology 1988; 63:369-372. 100. Koerner SK, Hagstrom JWC, Veith FJ: Transbronchial biopsy for the diagnosis of lung transplant rejection. Am Rev Respir Dis 1976; 114575-579. 101. Kondo Y, Cockrell JV, Kuwahara 0, et al: Histopathology of one-stage bilateral lung allografts. Ann Surg 1974; 180:753-759. 102. Kontos G, Adachi H, Borkon AM, et al: Successful four-hour heart-lung preservation with core cooling on cardiopulmonary bypass: A simplified model that assesses preservation. J Heart TranspkwIt 1987; 6:106-111. 103. Koyama I, Toung TJK, Rogers MC, et al: 0, radicals mediate reperfusion lung injury in ischemic 0, ventilated canine pulmonary lobe. J Appl Physiol 1987; 63:111-115. 104. Ladowski JS, Kapelanski DP, Teodori MF, et al: Use of autoperfusion for distant procurement of heart-lung allografts. Heart Transplant 1985; 4:330- 333. 105. La11 A, Graf PD, Nadel JA, et al: Adrenergic reinnervation of the reimplanted dog lung. J Appl Physiol 1973; 35:439-442. 106. Lanari A, Molins M, Croxatto 0: Homoinjertos de pulmon en perros. Tecnica y resultados funcionales y anatomicos. Medicina (Buenos Aires) 1951; 11:12-24. 107. Lawrence EC, Broussseau KP, Kurman CC, et al: Soluble interleukin-2 receptor levels in serum as a marker of rejection in heart-lung transplantation. Chest 1986; 89:S526 (abstract). 108. Lima 0, Cooper JD, Peters WJ, et al: Effects of methylprednisolone and azathioprine on bronchial healing following lung transplantation. J Thorac Cardiovasc Surg 1981; 82:211-215. 109. Lima 0, Goldberg M, Peters WJ, et al: Bronchial omentopexy in canine lung transplantation. J 7’horac Cardiovasc Surg 1982; 83:418-421. 110. Lincoln JCR, Barnes N, Gould T, et al: Pulmonary mechanics and surfactant following reimplantation of dog’s lung. Thor&~ 1970; 25255. 111. Lincoln JCR, Valenca LM, Kazemi H, et al: Serial perfusion and ventilation studies following reimplantation of the lung using xenon, pulmonary angiography, and bronchography. J Thorac Cardiovasc Surg 1970; 60:108-115. 112. Deleted in proof. 113. Magovern GJ, Yates AI: Human homotransplantation of left lung: Report of a case. Ann NYAcad Sci 1964; 120:710-728. 114. Mal H, Andreassin B, Fabrice P, et al: Unilateral lung transplantation in end stage pulmonary emphysema. Am Rev Respir Dis, in press. 115. Mathisen DJ, Grill0 HC, Vlahakes GJ, et al: The omentum in the management of complicated cardiothoracic problems. J Thorac Cardiovasc Surg 1988; 95:677-684. 116. Maurer JR, McClean PA, Zamel N, et al: Airway hyperreactitity in patients undergoing single lung and lung/heart transplantation. Am Rev Respir Dis 1987; 135A475 (abstract). 117. McCord JM: Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985; 312:159- 163. 118. Meshalkin EN, Sergievskii VS, Feofilov GL, et al: First attempts at surgical treatment of bronchial asthma by the method of pulmonary autotransplantation. Eksp Khir Anest 1964; 9:26-33. 119. Metras H: Note preliminaire sur la greffe totale du poumon chez le chien. C R Acad Sci (Paris) 1950; 231:1176-1178. 746

Curr

Probl

Surg

October 1989

120. Michelassi F, Schuette A, Landa L, et al: Pulmonary and systemic contribution to canine tracheobronchial blood flow. Ital J Surg Sci 1987; 17:105- 112. 121. Mills NL, Boyd AD, Gheranpong C, et al: The significance of bronchial circulation in lung transplantation. J Thorac Cardiovasc Surg 1970; 60:866-878. 122. Moeschl P, Lubec G, Keiler A, et al: Donor and organ specific evaluation of antibodies eluted from canine lung allografts rejected by immunosuppressively treated and untreated recipients. Respiration 1979; 38:12-17. 123. Moeschl P, Lubec G, Keiler A, et al: In vitro evidence of cellular and humoral immune responses following lung allotransplantation in canine recipients with and without immunosuppressive treatment. Eur Surg Res 1979: 11234-242. 124. Molokhia FA, Ponn RB, Aaimacopoulos PJ, et al: Microscopic and ultrastructural changes in unmodified canine lung allografts. Arch Surg 1971; 103:490-495. 125. Morgan E, Lima 0, Goldberg M, et al: Successful revascularization of totally ischemic bronchial autografts with omental pedicle flaps in dogs. J Thorac Cardiovasc Surg 1982; 84:204- 210. 126. Nakae S, Webb WR, Theodorides T, et al: Respiratory function following cardiopulmonary denervation in dog, cat, and monkey. Surg Gynecol Obstet 1967; 125:1285-1292. 127. Nasseri M, Eisele R, Stadtler K, et al: Neural supply of the autotransplanted lung with special reference to respiratory control after bilateral pulmonary reimplantation. Eur Surg Res 1970; 2:287-301. 128. Nelems JMW, Rebuck AS, Cooper JD, et al: Human lung transplantation. Chest 1980; 78:569-573. 129. Neptune WB, Weller R, Bailey CP: Experimental lung transplantation. J Thorac Surg 1953; 26275-289. 130. Noiclerc M, Metras D, Vaillant A, et al: Technique chirurgicale de la transplantation bi-pulmonaire. J Lyon Chirurgical, in press. 131. Novitzky D, Cooper DKC, Reichart B: Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987; 43:852-854. 132. Novitzky D, Wicomb WN, Cooper DKC, et al: Electrocardiographic, hemodynamic, and endocrine changes occurring during experimental brain death in the chacma baboon. J Heart Transplant 1984; 4:63-69. 133. Parks DA, Buckley GB, Granger DN: Role of oxygen free radicals in shock, ischemia, and organ preservation. Surgery 1983; 94:428-432. 134. Patterson GA, Cooper JD, Dark JH, et al: Experimental and clinical double lung transplantation. J Thorac Cardiovasc Surg 1988; 95:70-74. 135. Patterson GA, Cooper JD, Goldman B, et al: Technique of successful clinical double-lung transplantation. Ann Thorac Surg 1988; 4:626-633. 136. Patterson GA, Todd TR, Cooper JD, et al: Airway complications following double lung transplantation. J Thorac Cardiovasc Surg, in press. 137. Paul1 DE, Keagy B, Kron EJ, et al: Reperfusion injury in the lung presetved for 24 hours. Ann Thorac Surg 1989; 47:187-192. 138. Paul1 DE, Keagy B, Kron EJ, et al: Improved lung preservation using a dimethylthiouma flush. J Surg Res 1989; 46~333-338. 139. Peacock EE, Winkle WV: Wound Repair. Philadelphia, WB Saunders Co, 1976, pp 185-189. 140. Pearson FG, Goldberg M, Stone RM, et al: Bronchial arterial circulation restored after reimplantation of canine lung. Can J Surg 1970; 13:243-250. Curr Probl Surg, October

1989

747

141. Penketh A, Higenbottam T, Hakim M, et al: Heart and lung transplantation in patients with end stage lung disease. Br Med J 1987; 295:311-314. 142. Pinsker KL, Kamholz SL, Montefusco C, et al: Long-term functional adequacy of canine autografts after 24-hour preservation. Transplant Proc 1981; 13:715- 717. 143. Pinsker RL, Koerner SK, Kamholz SL, et al: Effect of donor bronchial length on healing. J Thorac Cardiovasc Surg 1979; 77:669-673. 144. Pinsker KL, Montefusco C, Yipintsoi T, et al: Total in vivo functional adequacy of canine lung autografts after 24-hour preservation. Transplant Proc 1979; 11:599-602. 145. Pio Roda CL, Strandberg JD, Baker JW, et al: Serial changes in pulmonary blood flow occurring during acute rejection of a lung allograft. J Thorac Cardiovasc Surg 1973; 65:88-93. 146. Popp AJ, Shah DM, Berman RA, et al: Delayed pulmonary dysfunction in head-injured patients. J Neurosurg 1982; 57:784-790. 147. Price-Thomas C: Conservative resection of the bronchial tree. J R Co11 Surg Edinb 1955; 1:169-186. 148. Prop J, Nieuwenhuis P, Wildevuur CRH: Lung allograii rejection in the rat: I. Accelerated rejection caused by graft lymphocytes. Transplantation 1985; 4025-30. 149. Prop J, Wagenaar-Hilbers JPA, Petersen AH, et al: Diagnosis of rejection in rat lung allografts by bronchoalveolar lavage. Transplant Proc 1987; 19:3779-3780. 150. Prop J, Wagenaar-Hilbers JPA, Petersen AH, et al: Characteristics of cells lavaged from rejecting lung allografts in rats. Transplant Proc 1988; 20:217-218. 151. Prop J, Wildevuur CRH, Nieuwenhuis P: Lung allograft rejection in the rat: II. Specific immunological properties of lung grafts. Transplantation 1985; 40:126- 131. 152. Rabinovich H, Zeevi A, Herlan D, et al: Functional studies on lymphocytes in bronchoalveolar lavages from canine lung allografts. Transplant Proc 1988; 2O(Supp1 1):836-838. 153. Rabinovich JJ: Re-establishment of bronchial arteries after experimental lung lobe autotransplantation. J Thorac Cardiovasc Surg 1972; 64:119-126. 154. Rabinovitch J, Kirpikov S, Morosova M: Conservation pulmonaire pendant 24 heures avec autogreffe retardee. Ann Chir: Chir Thorac Cardiovasc 1983; 37:572-576. 155. Reichart BA, Novitsky D, Cooper DKC, et at: Successful orthotopic heartlung transplantation in the baboon after five hours of cold ischemia with cardioplegia and Collins’ solution. J Heart Transplant 1987; 6:15-22. 156. Reid LM: Chronic obstructive pulmonary diseases, in Fishman AP (ed): Pulmonary Diseases and Disorders. New York, McGraw-Hill Book Co, 1988, pp 1247-1272. 157. Reitz BA, Wallwork JL, Hunt SA, et al: Heart-lung transplantation: Successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982; 306:557-564. 158. Rich S: Primary pulmonary hypertension. Prog Cardiovasc Dis 1988; 31205- 238. 159. Robin ED, Cxoss CE: Lung transplantation: Past, present, and future. Ann Intern Med 1966; 65:1138-1147. 160. Sacks SA, Petrisch PH, Kaufman JJ: Canine kidney preservation using a new perfusate. Lancet 1973; 1:1024-1028. 748

Curr Probl Surg, October 1989

161. Sanfillipo F, Vaughan WK, Spees EK, et al: Benefits of HLA-A and HLA-B matching on graft and patient outcome after cadaveric-donor renal transplantation. N Engl J Med 1984; 311:358-364. 162. Santillan-Doherty P, Odor-Morales A, Jasso-Victoria R, et al: Urinary thromboxane B, as an indicator of acute rejection in lung allotransplantation. Transplantation 1988; 451852-856. 163. Saunders NR, Egan TM, Chamberlain D, et al: Cyclosporine and bronchial healing in canine lung transplantation. J Thorac Cardiovasc Surg 1984; 88:993-999. 164. Scanlin TF: Cystic fibrosis, in Fishman AP (ed): Pulmonary Diseases and Disorders. New York, McGraw-Hill Book Co, 1988, pp 1273-1294. 165. Schafers JH, Frost AE, Waxman MB, et al: Cardiac innervation following double lung transplantation. Am Rev Respir Dis 1988; 137245 (abstract). 166. Schafers HJ, Todd TR, Ginsberg RJ, et al: Bronchial complications following single lung transplantation. J Thorac Cardiovasc Surg, in press. 167. Schreinemakers HJ, Weder W, Miyoshi S, et al: Direct revascularization of bronchial arteries for lung transplantation. Ann Thorac Surg, in press. 168. Scott J, Higenbottam T, Hutter J, et al: Heart-lung transplantation for cystic fibrosis. Lancet 1988; 2:192-194. 169. Shinoi K, Hayata Y, Aoki H, et al: Pulmonary lobe homotransplantation in human subjects. Am J Surg 1966; 111:617-628. 170. Shionozaki F, Kondo T, Fujimura S, et al: Technical establishment and detection of rejection in rat lung transplantation. Transplant Proc 1985; 17:244-247. 171. Siegleman SS, Dougherty JC, Hagstrom JWC, et al: Radiologic dissociation of alveolar and vascular phases of rejection in allografted lungs. Ann Thorat Surg 1971; 12:127-138. 172. Siegleman SS, Hadstmm JWC, Koerner SK, et al: Restoration of bronchial artery circulation after canine lung allotransplantation. J Thorac Cardiovasc Surg 1977; 73:792-795. 173. Slim MS, Yacoubian HD, Simonian SJ, et al: Bilateral reimplantation of canine lungs: Anatomical and physiological observations in a long term survivor. Ann Thorac Surg 1965; 1:755-759. 174. Slim MS, Yacoubian HD, Wilson JL, et al: Successful bilateral reimplantation of canine lungs. Surgery 1964; 55:676-683. 175. Starkey TD, Sakakibara N, Hagberg RC, et al: Successful six-hour cardiopulmonary preservation with simple hypothermic crystalloid flush. J Heart Transplant 1986; 5:291-297. 176. Staudacher V, Bellinazzo P, Pulin A: Primi rilievi su tentativi di reimpianti autoplastici e di trapianti omoplastici di lobi polmonari. Chirurgia (Milano) 1950; 5223-227. 177. Stevens PM, Johnson PC, Bell RL, et al: Regional ventilation and perfusion after lung transplantation in patients with emphysema. N Engl J Med 1970; 282245-249. 178. Stevens GH, Sanchez MM, Chappell GL: Enhancement of lung preservation by prevention of lung collapse. J Surg Res 1973; 14:400-405. 179. Stiller CR, Keown PA: Cyclosporine therapy in perspective. Prog Transplant 1984; l:ll-45. 180. Stoic V, Krause JR: Interleukin-2 receptor levels are increased in blood of heart transplant patients during infections. Diagn Clin Immunol 1987; 5:171-174. Curr Pmbl Sur5 October

1989

749

181. Stone RM, Ginsberg RJ, Colapinto RF, et al: Bronchial artery regeneration after radical hilar stripping. Surg Forum 1966; 17:109-110. 182. Strandberg JD, Pio Roda CL, Baker RR: Lung allografts in calves. Arch Surg 1973;106:196-200. 183. Suarez LD, Seindaro EE, Llera JJ, et al: Long term follow up and primary pulmonary hypertension. Br Heart J 1979; 41:702-708. 184. Sweeney MS, Sinnott JT, Cullison JP, et at: The use of OKT3 for stubborn heart allograft rejection: An advance in clinical immunotherapy? .I Heart Transplant 1987;6:324-328. 185. Taffel M: The repair of tracheal and bronchial defects with free fascia grafts. Surgery 1940; 856-71. 186. Tazelaar HD, Prop J, Niewenhuis P, et al: Obliterative bronchiolitis in the transplanted rat lung. Transplant Proc 1987; 19:1052. 187. The Toronto Lung Transplant Group: Sequential bilateral lung transplantation for paraquat poisoning. J Thorac Cardiovasc Surg 1985; 89:734-742. 188. The Toronto Lung Transplant Group: Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140-1145. 189. The Toronto Lung Transplant Group: Experience with single lung transplantation for pulmonary fibrosis. JAA4A 1988; 259:2258-2262. 190. Thorpe JE, Baughman RP, Frame Pf, et al: Bronchoalveolar lavage for diagnosing acute bacterial pneumonia. J Infect Dis 1987; 155:855-861. 191. Todd TR, Goldberg M, Koshal A, et al: Separate extraction of cardiac and pulmonary grafts from a single organ donor. Ann Thorac Surg 1988; 46:356-359.

192. Toledo-Pereyra LH, Condie RM: Lung transplantation: Hypothermic storage for 24 hours in a colloid hypoosmolar solution. J Thorac Cardiovasc Surg 1978;

76:846-852.

193. Toledo-Pereyra LH, Hau T, Simmons RL, et al: Lung preservation techniques Ann Thorac Surg 1977; 23:487-494. 194. Trimble AS, Bharadwaj B, Bedard P: Successful bilateral lung reimplantation in the dog. Can J Surg 1967; 16:89-93. 195. Trummer MJ, Benfield JR, Blumenstock DA, et al: A report of the lung transplant workshop-1970. Ann Thorac Surg 1971; 12:347-358. 196. Trummer MJ, Christiansen AH: Radiographic and functional changes following autotransplantation of the lung. J Thorac Cardiovasc Surg 1965; 49:1006-1014. 197. Tsai SH, Anderson WR, Haglin JJ, et al: Graft rejection after lung transplantation: A radiologic-pathologic study in the baboon. Radiology 1970; 94:121-125. 197a. Ullmann E: Experimentelle Nieren transplantation. Wein IUin Wschr 1902; 15: 281.

198. Van der Hyde MN, Verwers HR, Van Leusen R: Sluiten van een lekkende bronchusnaad na pneumonectomie wegens carcinoom bi j een chronische dialyse patient. Acta Chir Belg 1978; 77:271-274. 199. Vanderhoeft P, de Francquen P, Dubois A, et al: Anatomical basis of transmediastinal surgery on both lungs. Acta Chir Berg 1970; 69:149-157. 200. Vanderhoeft P, Dubois A, Lauvau N, et al: Block allotransplantation of both lungs with pulmonary trunk and left atrium in dogs. Thora,x 1972; 27:415-419. 201. Vanderhoeft RJ, Rocmans P, Nemry C, et al: Left lung transplantation in a patient with emphysema. Arch Surg 1971; 103:505-509. 202. Veith FJ: Lung transplantation 1970 (editorial). Ann Thorac Surg 1970; 9:580-583. 760

Cur-r

Probl

Surg,

October

1989

203. Veith FJ: Preservation of the lung. Transplant Proc 1974; 6:323-328. 204. Veith FJ, Crane R, Tomes M, et al: Effective preservation and transportation of lung transplants. J Thorac Cardiovasc Surg 1976; 72:97-105. 205. Veith FJ, Koerner SK, Siegleman SS, et al: Single lung transplantation in experimental and human emphysema. Ann Surg 1971; 178:463-476. 206. Veith FJ, Richards K: Improved technique for canine lung transplantation. Ann Surg 1970; 171:553-558. 207. Veith FJ, Richards K: Lung transplantation with simultaneous contralateral pulmonary artery ligation. Surg Gynecol Obstet 1969; 129:768- 774. 208. Veith FJ, Sinha SBP, Blumcke S, et al: Nature and evolution of lung allograft rejection with and without immunosuppression. J Thorac Cardiovasc Surg 1972; 63:509-520. 209. Veith FJ, Sinha SBP, Graves JS, et al: Ischemic tolerance of the lung: The effect of ventilation and inflation. J Thorac Cardiovasc Surg 1971; 61:804-810. 210. Virkkula L, Erola S: Use of omental pedicle for treatment of bronchial fistula after lower lobectomy. Stand J Thorac Cardiovasc Surg 1975; 9:287-290. 211. Vuillard P, Gadot P, Radice P, et al: Homogreffe pulmonaire bilaterale simultanee chez le chien. Presse iMed 1969; 77:1725-1726. 212. Wahlers T, Haverick A, Fieguth HG, et al: Flush perfusion using Euro-Collins solution vs cooling by means of extracorporeal circulation in heartlung preservation. J Heart Transplant 1986; 5:89-98. 213. Waldhausen JA, Daly WJ, Baez M, et al: Physiologic changes associated with autotransplantation of the lung.Ann Surg 1967; 165:580-589. 214. Wallwork J, Jones K, Cavarocchi N, et al: Distant procurement of organs for clinical heart-lung transplantation using a single flush technique. Transplantation 1987; 44:654-658. 215. Wang LS, Yoshikawa K, Miyoshi S, et al: The effect of ischemic time and temperature on lung preservation using a simple ex-vivo rabbit model for functional assessment. J Thorac Cardiovasc Surg, in press. 216. Warren BA, deBono AHB: The ultrastructure of early rejection phenomena in lung homografts in dogs. Br J E,xp Pathol 1969; 50:593-599. 217. Wewers MD, Casolaro MA, Sellers SE, et al: Replacement therapy for alpha1 antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316:1055-1062. 218. White JJ, Tanser PH, Anthonisen NR, et al: Human lung homotransplantation. Can Med Assoc J 1966; 94:1199-1209. 219. Wildevuur CR, Benfield JR: A review of 23 human lung transplantation by 20 surgeons. Ann Thorac Surg 1970; 9:489-515. 220. Yacoub MH, Khaghani A, Banner N, et al: Distant organ procurement for heart and lung transplantation. Transplant Proc 1989; 212548-2550. 221. Yamashita C, Oobo H, Tsuji F, et al: Lung transplantation: Effects of PGI, analogue on reimplantation response. Submitted for publication. 222. Zeevi A, Fung JJ, Paradis IL, et al: Lymphocytes of bmnchoalveolar lavages from heart-lung transplant recipients. J Heart Transplant 1985; 4:417-421.

Curr Probl Surg. October 1989

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