Perioperative Mortality and Primary Graft Failure

15 Barkley JE , Green MR. Bronchioloalveolar carcinoma. J Clin Oncol 1996; 14:2377-86 16 Auge r M, Katz RL, Johnston DA. Diffe re ntiating cytological features of bronchioloalveolar carcinoma from adenocarcinoma of the lung in fin e-needle aspirations: a statistical analysis of 27 cases. Diagn Cytopathol 1997; 16:253-57 17 Zaman SS , van Hoeven KH , Slott S, et al. Distinction between bronchioloalveolar carcinoma and hyperplastic pulmonary prolife rations: a cytologic and morphometric analysis. Diagn Cytopathol 1997; 16:396-401 18 Marchetti A, Buttitta F , Pellegrini S, et al. Bronchioloalveolar lung carcinomas: K-ras mutations are constant events in the mucinous subtype. J Pathol 1996; 179:254-59 19 Nuorva K, Soini Y, Kamel D, et al . p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis. Int J Cancer 1995; 64:424-29

Perioperative Mortality and Primary Graft Failure A s lung transplantation has become increasingly accepted in the management of end-stage cardiopulmonary disease, attention has focused mainly on late outcomes , particularly on the difficult problem of obliterative bronchiolitis. 1 The Registry of the International Society for Heart and Lung Transplantation2 for 1997 reported an average survival of 4.0 years after lung transplantation, as compared with an average survival of only 2.7 years at the beginning of this decade. The transplant surgery itself and the immediate postoperative period have become fairly routine. Nevertheless, closer inspection of the survival curves shows a precipitous decline in the probability of survival in the first 3 months after lung transplantation so that the 3-month survival rate drops to a disappointing 85%. 2 Even more disturbing, this high rate of perioperative mortality has not declined in recent years. 2 In contrast, the average survival after heari transplantation is 8.6 years, and the 3-month survival rate exceeds 90%.2 The main cause of perioperative mortality after lung transplantation has been given various names, such as pulmonary reimplantation response, graft ischemia, noncardiogen.ic pulmonary edema , reperfusion lung injury, allograft dysfunction, and graft failure.3 -·5 Regardless of the terminology, the postoperative course in these instances is characterized by pulmonary edema, severe hypoxemia, respiratory infection, and a high incidence of sepsis and nonrespiratory organ system dysfunction. Characteristically, the immediate postoperative chest radiograph and blood gases are satisfact01y, only to deteriorate in the first 12 to 24 h after surgery. The wea1y surgeon leaves the operating room proud of his well-functioning allograft, only to be disturbed several hours later

by the pulmonologist who informs him that the patient is now requiring 100% oxygen and 40 parts per million of nitric oxide. Less commonly, the lung may become edematous even in the operating room or may develop delayed unexplained radiographic haziness 5 days after transplantation. 4 In this context, the article in this issue of CHEST by Christie and coworkers (see page 51), which examines the incidence of primary graft failure after lung transplantation, is particularly relevant. The authors describe a 15% rate of graft failure, which in turn is associated with a very high mortality rate, lengthy hospitalization, and compromised recovery in survivors . The occurrence of graft failure did not correlate with any obvious variables related to either the donor or the recipient, nor did the occurrence of graft failure correlate with ischemic time or with degree of surgical experience. The predominant histologic finding was diffuse alveolar damage, but there were no clues as to possible etiology of the graft failure. Accordingly, the authors propose the term primary graft failure (PGF) as a clinically useful description, analogous to the term ARDS. The designation PGF carries no implication of underlying mechanism (such as reperfusion injury) and should serve to facilitate meaningful comparison of data among lung transplant centers. In addition to the definition of PGF, this study by Christie and coworkers nicely demonstrates some of the principles of early postoperative graft management. The data in Table 2 demonstrate that patients with postoperative radiographic haziness do not die from acute rejection and that the practice of treating diffuse radiographic infiltrates with a course of corticosteroids should be discouraged. Nevertheless, I am somewhat surprised that pathologic analysis did not reveal signs of aspiration or pulmonary emboli in the donor lungs related to the events of the donor's brain death. When an unused lung from a donor whose other lung was used for transplantation has been analyzed, one frequently finds evidence of aspiration injury, hemorrhage, focal pneumonitis, or intravascular thrombosis. Similar findings were reported by Husain and Hinkamp. 6 In other reported instances, the donor lungs directly transmitted pathogenic bacteria into the recipient thorax with adverse clinical consequences.' It is also good to remember that there are other known causes of graft failure that may be clinically occult. I and others have reported thrombus formation at the pulmonary venous anastomotic suture line or in tl1e left atrium. 8 •9 Such tl1rombi may have catastrophic consequences related to obstruction of pulmonary venous flow. These thrombi are not detected by transthoracic echocardiography and require transesophageal echocardiography, perfusion scans, or angiograms to CHEST/114/1 /JULY, 1998

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confirm their presence. 8 ·9 Ohoril0 reported four cases of adenovirus pneumonitis as a cause of graft failure. All infections were detected within 45 days of transplantation and were rapidly progressive and fatal in each instance.10 All four patients shared histopathologic features of necrotizing and hemorrhagic pneumonia in a background of exudative, diffuse alveolar damage. 10 Frost 11 reported a patient with strong evidence for hyperacute rejection as a consequence of preformed antibodies against the donor. Finally, postoperative gastroparesis and microaspiration have been implicated as a contributing factor in up to 35% of perioperative mortalities. 12· 13 From these considerations, it is apparent that there are still many perioperative issues to be resolved in clinical lung transplantation. These include optimizing donor lung function, selecting the most appropriate recipients, minimizing technical problems, and improving postoperative management. A recent multicenter trial suggests that blocking complement activation before reperfusion may attenuate lung injury after transplantation. 14 Other investigators have reported improved allograft function by stimulating cyclic adenosine monophosphate (with prostaglandin E 1 ) or cyclic guanosine monophosphate (with inhaled nitric oxide).1·5 For nitric oxide, at least, the clinical utility remains debated, because highly toxic oxidants may be generated during the quenching of nitric oxide by superoxide after onset of reperfusion. 16 By reducing perioperative complications, one hopes to increase further the average survival after lung transplantation. Larry L. Schulman, MD, FCCP New York Dr. Schulman is Associate Professor of Clinical Medicine, College of Physicians and Surgeons of Columbia University. Reprint requests: Larry L. Schulman, MD, FCCP, College of Physicians and Surgeons of Columbia University, PH 8 Center, Pulmonary Diagnostic Unit, 622 W ..168 St, Nett; York, NY 10032

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with outcome of transplanted contralateral lung. J Heart Lung Transplant 1993; 12:932-39 Low DE , Kaiser LR, Haydock DA, et al. The donor lung: infectious and pathologic factors affecting outcome in lung transplantation. J Thorac Cardiovasc Surg 1993; 106:614-21 Malden ES, Kaiser LR, Gutierrez FR. Pulmona~y vein obstruction following single lung transplantation. Chest 1992; 102:645-47 Leibov.>itz DW, Smith CR, Michler RE, et al. Incidence of pulmona1y vein complications after lung transplantation: a prospective transesophageal echocardiographic study. J Am Col! Cardiol1994; 24:671-75 Ohori NP, Michaels MG, Jaffe R, et al. Adenovirus pneumonia in lung transplant recipients. Hum Pathol 1995; 26: 1073-79 Frost AE, Jammal CT, Cagle PT. Hyperacute rejection following lung transplantation. Chest 1996; 110:559-62 Reid KR , McKenzie FN, Menkis AI-l, et al. Importance of chronic aspiration in recipients of heart-lung transplants. Lancet 1990; 336:206-08 Berkowitz N,Schulman LL, McGregor C, et al. Gastroparesis after lung transplantation: potential role in postoperative respirat01y complications. Chest 1995; 108:1602-07 Kes havjee SH, Davis RD , Zamora MR, et al. Inhibition of complement in human lung transplant reperfusion injury: a multicenter clinical trial [abstract]. J Heart Lung Transplant 1998; 17:43 Pinsky DJ, !\'aka Y, Chowdhmy NC, et al. The nitric oxide/ cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. Proc Nat! Acad Sci USA 1994; 91:12086-90 :\I aka Y, Roy DK, Smerling AJ, et al. Inhaled nitric oxide fails to confer the pulmonary protection provided by distal stimulation of the nitric oxide pathway at the level of cyclic guanosine monophosphate. J Thorac Cardiovasc Surg 1995; 110:1434-40

Pulmonary Vascular Disease Our Need to Understand

Tremains he etiology of prim pulmonary hypertension unknown. The reasons remain obscure my

REFERENCES 1 Banda K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and hea1i-lung transplantation: an analysis of risk factors and management. J Thorac Cardiovasc Surg 1995; 110:4-13 2 Hosenpud JD, Ben nett LE, Keck BM, e t al. The Regist1y of the International Society for Heart and Lung Transplantation: fourteenth offlcial repOii-1997. J Heart Lung Transplant 1997; 16:691-712 3 Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; 155:789-818 4 Anderson DC, Glazer HS, Semenkovich JW, et al. Lung transplant edema: chest radiography after lung transplantation- the first lO days. Radiology 1995; 195:275-81 5 Date H , Triantafillou AN, Trulock EP, et al. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996; 111:913-19 6 Husain AN, Hinkamp TJ. Donor lung pathology: correlation 8

why some patients with congenital heart disease develop irreversible pulmonary vascular disease, eg, Eisenmenger's syndrome, as well as why some patients with the scleroderma spectrum of diseases (including CREST syndrome, overlap syndrome, antiphospholipid syndrome), HIV infections, or exposure to appetite suppressants also develop progressive pulmonary vascular disease. Romberg, in 1891, described the histopathologic findings from a patient who died of primary pulmonary hypertension. Despite significant advances investigating the role(s) of various vasoactive mediators, as well as coagulation disorders and platelet-leukocyte-endothelial cell interactions in patients with various forms of pulmonary vascular disease, the answers to the quesEditorials