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Single and Double Lung Transplantation

Health Technology Assessment Reports 1991, Number 5

, D.O.

Created: .

Foreword

The Office of Health Technology Assessment (OHTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies. In most instances, assessments address technologies that are being reviewed for purposes of coverage by Federally funded health programs.

OHTA'S assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies. If an assessment has been prepared to form the basis for a coverage decision by a Federally financed health care program, it serves as the Public Health Service's recommendation to that program and is disseminated widely.

OHTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

  • Thomas V. Holohan, M.D.
  • Director
  • Office of Health Technology Assessment
  • J. Jarrett Clinton, M.D.
  • Administrator, AHCPR
  • Question regarding this assessment should be directed to:
  • Office of Health Technology Assessment
  • AHCPR
  • Executive Office Center, Suite 400
  • 2101 East Jefferson Street
  • Rockville, MD 20857
  • (301) 227-8337

Introduction

Allogeneic lung transplantation (LT) involves the grafting of one or both lungs from a brain-dead or cadaveric donor to a selected patient with end-stage pulmonary vascular or parenchymal disease who has failed standard therapies and for whom no other treatment option exists.(1-3) The first use of a living related donor for LT using a lobe rather than a whole lung has already been reported, (4). and the use of live donors, related or unrelated, will probably evolve as a common clinical option.(5,6)

The transplant is used in three clinical procedures: combined heart-lung transplantation (HLT) (the subject of a separate assessment); single lung transplantation and double lung transplantation (DLT), either performed en bloc with the bronchial tree or including transplant of each lung separately with bilateral bronchial anastomoses.(3)

End-stage pulmonary disease is a term defining irreversibility of severe anatomic changes in the lungs leading to incapacitating clinical manifestations and eventual respiratory failure (often associated with right ventricular failure). The lungs have exhausted all reserves for gas exchange, and patients frequently require oxygen or assisted ventilation therapy to sustain life.(7) Examples of such life-threatening diseases are severe emphysema, pulmonary fibrosis, cystic fibrosis (CF), and pulmonary hypertension resulting from arterial or venous vascular disease or congenital heart defects.(8,9) Lung transplantation can potentially be applied to thousands of patients yearly who might otherwise die from these acute or chronically progressive end-stage pulmonary diseases.

Chronic obstructive pulmonary disease (COPD) affects approximately 10 million people in the United States, the majority of whom have emphysema.(10) For those patients having severe progressive disease relatively early in life, LT offers the only possibility of preventing a premature demise.(11) Emphysema may also be secondary to an inherited deficiency of a [alpha](1)-antitrypsin (AAT), which affects an estimated 40,000 Americans.(12,13)

Primary pulmonary hypertension affects relatively young persons (mean age at diagnosis is 34), but the prognosis of these patients is poor, and only 20 survive 5 years.(14)

The prevalence of pulmonary fibrosis is estimated to be 3-5 cases per 100,000 population, and the disease in these patients generally runs an aggressive and usually fatal course.(15)

Cystic fibrosis is a common multivisceral recessive genetic disease having an incidence of 1 case per 2,000 in white and 1 case per 17,000 in black births.(16) There are an estimated 20,000 cases in the United States (including 2,000 adults) and approximately 1,000 new cases annually.(17) There is no medical treatment for these patients other than supportive care, and pulmonary disease as a consequence of exocrine gland obstruction by viscous secretions commonly results in bronchiectasis, peribronchial fibrosis, and airway obstruction.(17,18) Survival in patients with CF has dramatically increased in the past two decades secondary to improvement in antibiotics, nutritional management, physiotherapy, and specialized centers for treatment. However, 50 of patients die of respiratory failure by the age of 16, and the others rarely survive longer than 30 years.(15-18)

Despite the limited availability of suitable donor lungs, which restricts the application of this technology, (19-21). there has been a dramatic increase in the number of lung transplants performed in the United States in recent years: 32 in 1988, 84 in 1989, approximately 200 in 1990, and an estimated 500 to be completed in 1991 (see Figure). (22). The estimated cost of an LT is $150,000 in the first year and $20,000 annually thereafter.(23).

Figure. Annual lung transplants.

Figure

Figure. Annual lung transplants.

In addition to the relatively standardized surgical technique described by Cooper et al, (24-26). successful LT involves a large team of professionals attending to patient and donor selection, preoperative and postoperative rehabilitation, lifelong immunosuppression, and long-term followup.(25)

Background

Progress in LT has lagged behind that of other solid organ transplantation in part because of a lack of a suitable experimental model (the transplantation of normal lungs into nondiseased experimental animals is dramatically different from the transplantation of lungs into chronically ill humans(27). ). The initial poor results of LT (survival < 1 month) accounted, in part, for the hiatus in clinical interest in LT between 1963 and 1982, when the first "long-term" success was reported.(28-31)

The lung is a very fragile organ. During transplantation, it is at increased risk for infection because of exposure to organisms in the atmosphere. Lung allografts are unique among solid organ transplants in that they do not have their systemic arterial blood supply reconstructed at the time of surgery.(31,32) The fine network of bronchial vessels is interrupted and are not amenable to reattachment.(24,28) In the absence of positive intervention, the airway is at risk for ischemic complications until local adequate revascularization (usually requiring 2-3 weeks) can occur across the healing bronchial anastomosis).(26,28,33,34). The experience with primates at Standford University suggested that reconstruction of the bronchial arteries is probably required to ensure a slough-free donor bronchus, decreasing the risk of dehiscence.(35) However, the technique of LT has rarely included direct microsurgical methods of reestablishing bronchial circulation and these have been almost universally unsuccessful because of the small caliber of the vessels.(31,36,37)

Early concerns about LT included the uncertainty of recurrent disease, especially in patients with CF or interstitial fibrosis. Poor results in some of the early clinical experiences were associated with a ventilation/perfusion (V/P) imbalance.(38,39) In addition, there were fears that SLT would not provide sufficient pulmonary function and adaptation to the normal cardiac output without abnormal elevation of pulmonary artery pressure.(40) To date, it appears that these concerns were exaggerated. Recurrent disease has not been reported, the ability of SLT to provide total respiratory function has been abundantly demonstrated in preclinical studies and confirmed in humans, and it has been shown that significant V/P imbalance does not occur in the absence of other adverse conditions, e.g., infection or rejection, which may themselves be prevented or respond to treatment.(11,41,42)

The surgical feasibility of LT has been based largely on experiments in normal animals.(28,43) The operative techniques of LT were derived from canine models, and the first successes were reported in 1950 by Metras(44). in France and in 1954 by Hardin and Kittle(45). in the United States.

After extensive transplantation experience in more than 400 dogs, Hardy and associates(46). performed the first human SLT in 1963. Although the patient survived only 18 days, adequate lung function was established, and LT was thus demonstrated to be feasible in humans.

Two 1970 reviews of LT noted no long-term survivors in the 25 transplants performed to that time.(42,47) In subsequent reviews of more than 40 cases of LT through 1985 (including 3 HLT and 4 lobe transplants) reported by 26 teams worldwide, the median survival time was 8.5 days, and only 2 patients survived longer than 2 months.(1,48,49) The longest survivors (6 and 10 months) obtained significant palliation.(29,43) Most patients died within days or weeks from respiratory failure, pulmonary sepsis, rejection, or bronchial anastomotic complications.(47,48)

Prior to 1980, there were important technical advances including extracorporeal bypass, improved positive end-expiratory pressure techniques, fiberoptic oximetry and bronchoscopy, and the introduction of cyclosporine immunosuppression.(43,49,50) Short-term data had accumulated from both animal and human LT experience demonstrating that adequate (but not normal) respiratory function could be maintained despite pulmonary denervation.(37,42,51). However, the major limiting factor in LT still appeared to be bronchial anastomotic complications.(26,48)

Although ischemia is the primary source of such airway complications, immunosuppressant effects on bronchial anastomotic healing also play a significant role.(52,53) These airway complications include necrosis, strictures, dehiscence, and the development of a retrotracheal airspace.(54)

Bronchial anastomotic complications secondary to ischemia following LT are in sharp contrast to the situation following HLT, wherein consistent satisfactory tracheal anastomotic healing is almost assured.(38,55) This is attributed to preservation of mediastinal collateral arterial circulation from the coronary arteries through the pericardium and directly into the bronchial circulation of the lower trachea and carina.(54,56)

An early major technical advance in LT, introduced by Metras, (44). was related to the high incidence of thrombosis of the pulmonary venous anastomosis. This surgical innovation involved transecting a cuff of donor left atrium including the ostia of the pulmonary veins, thereby avoiding the need for anastomosis of these vessels.

The majority of early LT recipients who lived more than 2 weeks died in the third week from disruption of the bronchial anastomosis. The recognition that a significant proportion of the major complications contributing to the relatively poor success of LT was related to immunosuppressant steroid inhibition of bronchial anastomotic collagen synthesis and wound healing, in addition to the local ischemic problem, prompted additional canine experiments. This led to the reduction or elimination of routine early use of steroids in the immunosuppressive regimens and the use of omental pedicle flaps (bronchial omentopexy) to promote bronchial revascularization and physically support the anastomotic site to prevent bronchovascular or bronchopleural fistulae.(28,36,53,57)

The use of the omentum as a vascularized pedicle to wrap the bronchial anastomosis is now commonly performed as a highly successful technique to promote bronchial integrity.(54) Collateral circulation between the omental and bronchial vessels is often rapidly accomplished within a few days rather than 2-3 weeks, and problems of bronchial anastomotic healing have been dramatically reduced.(29,36,49)

The first long-term survivor with an allografted lung was a patient subjected to HLT who remained alive and well 10 months after surgery (reported by the Stanford University group in 1982) (31) The first long-term successes with SLT were reported by the Toronto Lung Transplant Group in 1986.(49) Two patients were alive and well at 26 months and 14 months after the procedure.

Single lung transplantation was initially introduced and, on the basis of early clinical experience, recommended as a treatment for restrictive interstitial lung disease.(49,55,58) The ideal candidates for SLT, i.e., those with end-stage pulmonary fibrosis, generally do not have chronic pulmonary infections. The reduced compliance and increased vascular resistance of the remaining fibrotic lung facilitate preferential ventilation and perfusion of the transplanted lung, which in turn increase pulmonary artery to bronchial artery blood flow and decrease the likelihood of airway ischemia.(25,30,32,49) Patients with emphysema were thought to be poor candidates for SLT because of the belief that hyperexpansion of the native lung and mediastinal shift would result in restricted ventilation of the transplant.(25,33) However, in practice this did not present a significant problem. Therefore, end-stage emphysema patients (especially those with AAT deficiency) as well as patients with pulmonary hypertension or COPD are currently regarded as candidates for SLT.(5,8,27,59-61)

Single lung transplantation is almost universally regarded as unsuitable for patients with chronically infected lungs (e.g., those with CF or bronchiectasis), which remain a focus for continuous sepsis, especially in the environment of immunosuppression.

Although transplantation of both lungs without the heart is technically more complex than HLT, the value of preservation of the recipient's heart has become apparent.(62). Experience from investigations of DLT has evolved a technique to avoid the problems and need for replacing the heart in patients having only end-stage parenchymal pulmonary disease for whom HLT was the only other treatment option available.(19,63-65)

In 1971, Veith and associates described a dog model for bilateral simultaneous lung allotransplantation.(66) An en bloc DLT in dogs was first described by Vanderhoeft et al in Belgium in 1972.(67) This experimental technique was further developed by Dark and the Toronto Lung Group in 1986, (68). and it was introduced clinically by Patterson and associates in 1988.(64)

Double lung transplantation was initially performed in patients with obstructive lung disease, based on the belief that such patients were not suitable for SLT because of V/P imbalance and crowding of the transplant by hyperinflation of the native lung.(33,56) More recent experience indicates that SLT achieves very satisfactory results in such patients.(21,61,69) Double lung transplantation is now applied to patients with end-stage pulmonary disease and adequate cardiac function who are not candidates for SLT.(62,64) These patients commonly have bilateral pulmonary sepsis, COPD, CF, or pulmonary hypertension.(24) While the technical feasibility of DLT has been established, the incidence of airway complications is higher than that associated with SLT as a consequence of a greater bronchial area subject to ischemia.(33) In addition, after DLT the pulmonary artery flow is equally distributed to each lung; therefore, collateral flow to each lung is reduced, in contrast to the situation described after SLT.(32)

Recent modifications in the technique of DLT have included bilateral sequential transplantation of the lungs, which reduces the requirement for cardiopulmonary bypass during en bloc procedures(30,59). and substitutes bilateral bronchial anastomosis (without omentopexy) for the tracheal anastomosis, which itself was associated with significant airway problems.(3,32,70)

Rationale

The feasibility of LT has been amply demonstrated in animal experiments and humans.(39,71) Prior to the development of successful LT for selected patients with progressive end-stage parenchymal or pulmonary vascular disease who have failed other therapies, HLT was the only other therapeutic option for an otherwise fatal disease.(7,9,64) Proponents of LT suggest that recent experience demonstrates the risk-benefit ratio to be favorable and to be comparable to that achieved by the transplantation of other major organs, i.e., kidney, heart, liver, and combined heart-lung.(72) As an alternative to HLT, SLT or DLT permits an economy of donor organs by allowing the heart or other lung to be used for another recipient, and it avoids the complications associated with the cardiac portion of HLT, including heart rejection, and the development of accelerated coronary artery disease. These procedures are associated with fewer hemodynamic complications, and they also eliminate the need for the relatively rare donor with suitable cardiac and pulmonary function.(54,65)

Review of Available Literature

In the two decades subsequent to the initial report of a human LT by Hardy et al(46). in 1963, only 2 patients among the 40 who underwent LTs worldwide survived beyond 2 months, and only 1 survived the hospitalization.(5,73) More recent data, (30,49). following the reports of successful SLT in 1986 and 1988 by the Toronto Lung Transplant Group, indicate 8 of 11 patients alive and well up to 44 months postoperatively.(49,74) By January 1989, the Toronto experience involved a total of 16 patients and 12 "long-term" survivors. The longest SLT survivor died of renal failure 6.25 years after the operation.(5) The first successes of DLT were also reported by the Toronto Group (1988-89) and involved seven patients, six of whom survived and were discharged from the hospital having good pulmonary function.(73) An update of the Toronto experience to July 1989 comprises a total of 24 SLTs and 17 DLTs.(69) A recent paper from the University of Mississippi, (75). involving six DLTs and three SLTs, described an early mortality of 33. In the discussion following this paper, Grover presented his experience with SLT in 13 patients at the University of Texas, San Antonio. Three patients died: one of renal failure at 4 months, and two of cytomegalovirus (CMV) infection at 30 and 40 days after operation. In the remaining 10 patients, no bronchial complications developed, although survival or followup data were not reported. A current review of the LT experience from Washington University involving 50 consecutive patients receiving transplants between August 1989 and November 1990 indicated only two hospital deaths and a 92 survival rate at a mean followup time of 8 months.(21). A summary of the recent LT experience in 140 patients is represented in the Table. These data are derived from a small group of centers using selected patients with, in most cases, a relatively short-term followup.

Table. Summary of recent lung transplant experience.

Table

Table. Summary of recent lung transplant experience.

Morphologic, x-ray, and functional changes resulting from surgical trauma, ischemia, denervation, and interruption of vascular and lymphatic networks have been termed the "reimplantation response."(43). These changes, which can mimic rejection, generally peak within 3 days postoperatively and regress within 3 weeks, during which time there is a transient impairment of ventilation and compliance.

Airway complications, graft failure, and rejection episodes are serious risks of LT and represent significant causes of transplant failures. However, postoperative infection remains the greatest threat to the long-term survival of LT recipients.(71,78-80). In 1988, infections were reported as being responsible for 75 of all deaths after LT, as the transplanted lung appears to be more susceptible to infection than the lung in a comparably immunosuppressed heart transplant recipient.(81) It has been hypothesized that lung allografts are relatively more susceptible to infection because of impaired responses of the alveolar macrophages of the host.

Lung transplantation patients are not highly immunoreactive, presumably because of their long-term chronic illness and hypoxia,. Therefore, lower levels of immunosuppressant drugs may be needed than for heart, liver, or kidney transplants.(73) However, lifetime immunosuppression is mandatory and is regarded as the major cause of susceptibility to infection in the allograft. Virtually any pathogen can be involved. Bacterial, CMV, Candida, and Pneumocystis carinii infections are especially prevalent in these patients.(9) Immunosuppression occasionally prevents rejection episodes and effectively modifies most rejection episodes to mild and reversible forms.(43)

Obliterative bronchiolitis, seen in approximately 50 of HLTs, (54,82). is infrequently observed after SLT (but has not been reported with DLT) and is regarded as a probable manifestation of chronic lung rejection or CMV infection.(9,69,83-85) The differential diagnosis between rejection and infection is sometimes difficult and imprecise, especially when rejection and infection occur together; often a transtracheal or transbronchial biopsy is the most suitable method for detecting rejection episodes, infection, or obliterative bronchiolitis.(2,85,86) In the diagnosis of rejection, transbronchial or transtracheal biopsies have a specificity of 80-100 and a sensitivity of approximately 70.(56,84,87) A universal grading system for biopsy interpretation does not currently exist, (88,89). although such a system could promote improved patient care and the development of alternative therapies for rejection.(84)

Accelerated atherosclerosis in the pulmonary vasculature, similar to that seen in the coronary arteries of heart transplant recipients, has also been reported and is believed to be a manifestation of chronic rejection.(9)

CF = cystic fibrosis; COPD = chronic obstructive pulmonary disease; DLT = double lung transplantation; NR = not reported; SLT = single lung transplantation

Discussion

According to current data provided by the Registry of the International Society for Heart and Lung Transplantation, a total of 447 SLTs and 120 DLTs have been reported by 83 transplant centers worldwide.(90) More than 70 of all LTs have been performed since 1989. The age of LT recipients ranged from 2 months to 67 years (mean age, 44). The most frequent indication for SLT has been pulmonary fibrosis, and for DLT, emphysema or CF. Currently, almost one-third of SLT recipients are patients with emphysema. Increasing numbers of patients with primary pulmonary hypertension or Eisenmenger's syndrome are now receiving SLT rather than HLT. Other indications for LT reported to the Registry include sarcoidosis, scleroderma, acute respiratory failure, bronchiectasis, pulmonary thromboembolic disease, hemosiderosis, Wegener's granulomatosis, histiocytosis X, systematic lupus erythematosus, leiomyosarcoma of the pulmonary artery, lymphangioleiomyomatosis, and primary pulmonary hypertension. In 1991, the reported operative mortality for SLT was 19 and for DLT, 17.(90) Intraoperative technical complications and cardiac complications (myocardial infarction or cardiac arrest) accounted for approximately one-third of all deaths. In that same report, (90). infection is cited as the additional cause in 33 of early deaths and 45 of the deaths. Rejection has been reported as a cause of 19 of all death and 50 of deaths occurring more than 6 months posttransplant.

Retransplantation has been relatively infrequent (7). Indications for retransplantation have included graft failure, acute or chronic rejection, and bronchiolitis obliterans. One-year actuarial survival is reported to be 67 for SLT(n = 109) and 57 for DLT (n = 22) (90)

The above data indicate that since 1983, considerable experience with LT has been achieved, and it has been applied as an option for the treatment of end-stage pulmonary disease. Despite the high rate of infections and problems related to the relatively short organ preservation time for LT, factors contributing to the recent improved survival time of patients undergoing LT have derived from advances in surgical and nursing techniques, immunosuppression, postoperative management (including more effective methods for diagnosing and treating infection and rejection), and, in large part, refinements in patient selection criteria.(3,49,52,57,59) However, the definitive evaluation of Lt for various subsets of patients will require clinical trials to determine the relative risks and benefits of SLT and DLT for such subsets.(11,57)

At present, specific procedure-related criteria for the optimal treatment of many of these patients have not been clearly established, (43,57,71,91,93). Patient selection criteria reported in the medical literature from various institutions, as well as opinions provided in response to the Federal Register notice of this assessment, have specified a broad range of disease categories and patient characteristics that make it infeasible to definitively discern which patients with which diseases are best suited for one or another transplant procedure. For example, the transplant community has not yet arrived at a level of consensus on this issue which would avoid such situations as a patient being rejected on the basis of age at one institution, yet accepted at another center. The maximum acceptable ages specified by many centers vary by as much as 15 years (vide infra). Without convincing clinical data supporting such criteria, patient selection on that basis becomes ethically as well as medically problematic, particularly if public funds are utilized to reimburse treatment.

Moreover, it is not possible to extract specific patient selection criteria from the various published series of lung transplantation with a high degree of confidence that such criteria would be clearly defensible or that they would not be rendered obsolete within a short time, given the rapid development of this technology. Additionally, a significant number of such abstracted criteria would likely conflict with alternative selection criteria employed by transplant centers that have demonstrated satisfactory outcomes.

In the event that valid and reliable patient selection criteria may not be directly developed from the published medical and scientific literature, it is not unreasonable to utilize expert clinical opinion as an alternative until such time as sufficient data have been accumulated to supplant it. The National Institute of Health has developed suggested criteria (vide infra) to this point.

Objective data are available to permit a logical and scientifically defensible derivation of institutional selection criteria. Paramount among these are improved patient outcomes in terms of survival rates. Survival figures provide suitable baseline standards for appropriate quality of care and predicted health outcome. The published literature indicates that a 1-year survival rate of 65 is attainable by the majority of experienced transplant centers. Concordant with survival rate statistics is the number of transplants performed. For LT there cannot yet be derived a mathematically predictable relationship between survival rates and the annual number of cases transplanted. The data cited in this assessment suggest that those centers with very limited experience have reported outcomes generally inferior to more experienced programs. More important, the reliability of outcome data increases as the sample size increases; that is, the probability that a reported statistic accurately predicts future outcome is far greater when based on larger versus smaller numbers of patients. For instance, the standard error of a mean is inversely proportional to the square root of the size of the sample: [square root] of the [sum] (X - micro-) (2)/N. A fourfold increase in sample size (e. g., from 5 to 20 transplants) will provide a twofold reduction in error of estimation. For these reasons, and in view of the fact that patient safety must necessarily be the primary consideration, the experience requirements recommended by the National Institutes of Health may be utilized, pending the development of data sufficient to address that point. While new program development is undeniably impeded by such outcome and experience requirements, it is beyond the scope of his assessment to address that issue. A review panel of individuals with recognized expertise in the area may be utilized to certify program initiation on a probationary basis while such data are accumulated. In that instance, the review panel may provide certification on the basis of the experience and demonstrated performance of the transplant team members and supporting personnel and the organizational commitment of appropriate resources for such a demanding treatment modality. However, lung transplantation is an innovative technology and is inappropriate for an entry level program; consequently, institutions should have demonstrated capability and acceptable performance in other transplant procedures.

Associated services required for optimal results in LT include documented expertise in pulmunary medicine, cardiology, immunology, infectious diseases, a psychiatric service experienced in problems incident to organ transplantation, an anesthesia service experienced in transplantation, histopathologic expertise necessary for rapid and accurate diagnosis of organ rejection, and intensive care facilities appropriate to the LT procedure. Such services must be formally dedicated to provide support to the LT program. In addition, each institution should be able to provide a specific patient selection protocol with documented rationale for each criteria chosen.

The scarcity of suitable organ donors and the current problems of organ preservation continue to limit the expansion of LT.(19,21) As a result of the common occurrence of pulmonary edema, aspiration, and pneumonia in brain-dead patients, it is estimated that only 5-10 of available donors have lungs considered acceptable for transplantation.(19,25,71,73)

Late deaths following LT are most commonly due to opportunistic infections and/or chronic rejection, and problems associated with mandatory lifelong immunosuppression continue as subjects of serious investigation.(69) Acceptable long-term clinical results currently depend on adequate methods to prevent graft rejection, and this ideal has yet to be achieved by the current immunosuppressive regimens.(93)

The National Institutes of Health (February 1991) states in an extensive memorandum that LT in selected patients by experienced teams yields significant increases in survival and quality of life.

Patient selection criteria must be based upon the critical medical need for the transplantation and the maximal likehood of a successful clinical outcome. Adverse factors must be absent or minimal, and affirmative criteria must be fulfilled.

Affirmative criteria include:

  • a) The patient must have irreversible, progressively disabling, end-stage pulmonary or cardiopulmonary disease (for example, less than a 50 likelihood of survival for 8 months). Prognosis otherwise must be good for both survival and rehabilitation.
  • b) All other medical and surgical therapies that might be expected to yield both short- and long-term survival comparable to that of transplantation must have been tried or considered.
  • c) The patient must have a realistic understanding of the range of clinical outcomes that may be encountered.
  • d) Plans for long-term adherence to a disciplined medical regimen must be feasible and realistic for the individual patient.

Many factors must be recognized as exerting an adverse influence upon the outcome after transplantation. A patient who meets the criteria above and is free of the adverse factors cited below is considered a good candidate for transplantation. Some of the factors cited below have important qualifications. It is recognized that some patients who may not be considered "good candidates" might also benefit from transplantation, but the likelihood or extent of benefit is thought to be significantly less.

Adverse factors include:

  • a) Acutely ill patients (i.e., with serious exacerbation of chronic end-stage disease or with non-chronic end-stage disease) or those currently requiring mechanical ventilation for more than a very brief period (because there is difficulty in adequate assessment, a propensity for infection, and likelihood for poor results).
  • b) Significant systematic or multisystem disease (because the presence of multiorgan involvement limits the possibility of full recovery and may compromise the function of the newly transplanted organ(s)).
  • c) Extrapulmonary site of infection (because of the probability of recrudescence once immunosuppression is instituted).
  • d) Hepatic dysfunction even secondary to right ventricular failure, such as bilirubin exceeding 2.5 mg/mL (because of hepatotoxicity of many posttransplant medications and complications due to coagulopathies, hepatic encephalopathy, infection, poor wound healing, and increased postoperative mortality).
  • e) Renal dysfunction, such as preoperative serum creatinine greater than 1.5 mg/dL or a 24-hour creatinine clearance less than 50 mL/min, except that with severe pulmonary hypertension creatinine clearance as low as 35 mL/min may be acceptable if intrinsic renal disease is excluded.
  • f) Systemic hypertension that requires multidrug therapy for even moderate control (for example, multidrugs to bring diastolic pressure below 105 mm Hg), either at transplantation or at the development of end-stage heart-lung disease (because of the substantial exacerbation of hypertension with posttransplantation drug regimen).
  • g) Cachexia, even in the absence of major end organ failure (because of the significantly less favorable survival of these patients).
  • h) Obesity, with weight being an increasingly severe adverse factor as the patient exceeds 20 of ideal weight for height and sex (because of more difficult postoperative mobilization and impaired diaphragmatic function, as well as the difficulty of weight control once corticosteroid immunosuppressant is instituted).
  • i) A history of behavior pattern or psychiatric illness considered likely to interfere significantly with a disciplined medical regimen (because a lifelong medical regimen is necessary requiring multiple drugs several times a day, with serious consequences in the event of their interruption or excessive consumption).
  • j) Continued cigarette smoking or failure to have abstained long enough g., at least 1 or 2 years) to indicate low likelihood of recidivism (because of the expected detrimental effects of smoking on the transplanted organs).
  • k) Previous thoracic or cardiac surgery or other bases for pleural adhesions, depending upon the site of thoracotomy/sternotomy, the degree of adhesions, and the type of transplant anticipated (because of scar tissue and the propensity for inadequately controllable bleeding).
  • l) Age beyond 50 or 55, that is, a patient has to be extremely "young for his/her age" if a double lung transplantation is envisioned in one who is over 50 or if a single lung transplantation is envisioned in one who is over 55 (because of greater complications beyond these ages unless this standard is used).
  • m) Recent or current history of gastrointestinal problems (because of common postoperative gastrointestinal problems and hemorrhage).
  • n) Chronic corticosteroid therapy that cannot be tapered and discontinued prior to transplantation (because of the increased risk of tracheal or bronchial dehiscence in the early postoperative period).
  • o) Chronic pulmonary infection (as with bronchiectasis, chronic bronchitis, or cystic fibrosis), a contraindication for single lung transplantation (because of the great likelihood of the infection extending from the contaminated native lung into the transplant lung), and the patient must meet the criteria and risk-benefit considerations of double lung transplantation.
  • p) Significant heart disease (for example, substantial irreversible right ventricular disease or significant coronary artery disease) requiring that the patient meet the criteria and risk-benefit considerations for lung transplantation and concurrent repair of the cardiac abnormality which may be appropriate in unusual circumstances, as in some situations with Eisenmenger's syndrome.

Single lung transplantation appears to be effective for many or most cases of end-stage obstructive, restrictive, or vascular pulmonary disease, except where the remaining lung is infected, in which case both lungs should be replaced. The recommended institutional and team experience for LT is at least 20 patients having LT and/or HLT (10 of whom should have undergone transplantation more than 12 months earlier) who achieve an actuarial survival of no less than 65 at 1 year.

Institutional and team experience should be requirements somewhat along the lines of the heart transplantation criteria of the Health Care Financing Administration (HCFA) and the Civilian Health and Medical Program of the United States. Primary emphasis should be on institutional and team experience and success.

The institutional and team experience should be based on all lung and heart-lung transplants performed since January 1, 1987, both for number of patients and survival.

The clinical team must be experienced and successful, and it must have continuing experience. Factors in favor of concentration of experience include the more equitable and efficient utilization of donor organs, better opportunity for advancing the field of transplantation and more efficient utilization of health care resources.

In response to the Federal Register notice of this assessment(94). and the solicitation of information and opinions from organizations and institutions involved with LT, the Office of Health Technology Assessment has received the following input:

Stanford University School of Medicine (November 1990) no longer regards SLT and DLT as investigational procedures. Their stated indications for SLT are pulmonary fibrosis, COPD, emphysema secondary to AAT deficiency, and pulmonary hypertension. Their indication for DLT is bilateral septic pulmonary disease. All patients should have end-stage pulmonary disease and a life expectancy of 18-24 months, be younger than age 56, in otherwise good health, and have the capacity for full rehabilitation. Contraindications for LT include acute illness or respirator or steroid dependence, significant systemic or multisystem disease, drug or alcohol abuse, or the presence of chemical or surgical "pleurodesis."

Northwestern University Medical School (December 1990) considers LT an effective procedure, indicated for oxygen-dependent patients aged 18-65 who are free of infection and have a life expectancy of less than 24 months as predicted by pulmonary function tests. Indications for SLT are restrictive or obstructive pulmonary disease and primary pulmonary hypertension. Double lung transplantation is indicated for patients with CF, AAT deficiency, or severe COPD.

Mayo Clinic (December 1990) states that SLT is safe and effective for pulmonary fibrosis, obstructive lung disease, and pulmonary hypertension. They state that DLT may be useful for septic lung disease; however, it is too early to judge its effectiveness, and this procedure continues to be regarded as experimental.

Washington University School of Medicine (December 1990) states that both SLT and DLT are effective for patients with CF, emphysema, or pulmonary fibrosis who have progressive disease and no alternative treatment options. Single lung transplantation for pulmonary hypertension with or without Eisenmenger's syndrome requires additional experience and caution and is regarded as investigational.

Humana Heart Institute International (January 1991) states that LT is indicated for patients with end-stage pulmonary disease whose condition is deteriorating, who are not responding to medical treatment, and who have a limited life expectancy. Contraindications for LT include the presence of life-limiting or significant risk-enhancing conditions.

University of North Carolina School of Medicine (January 1991) states that LT is a reasonable therapeutic option for patients with end-stage lung disease and no longer considers the procedure to be experimental.

Virginia Heart Surgery Associates (January 1991) consider LT for patients younger than age 60, with progressive end-stage parenchymal or vascular lung disease who have a life expectancy of less than 18 months, are not amenable to medical therapy, and are in otherwise good health.

Massachusetts Consortium for Lung Transplantation (January 1991) states that LT is a successful and viable therapeutic option for patients with end-stage pulmonary disease. In addition the consortium believes the risks of LT are similar to those encountered with other solid organ transplants.

University of California, San Diego (January 1991) has had an Lt program for only 1 year and experience with only four patients, in whom there was no operative mortality. They believe that specific selection criteria for LT are evolving and currently are a matter of clinical judgment. Their current indications for DLT are in patients with bilaterally infected lungs.

Inland Northwest Thoracic Organ Transplantation Program (January 1991) states that survival rates of LT are comparable to those of HLT and that "both procedures should be reimbursed by third-party carriers."

University of Minnesota (January 1991) has had an LT program since January 1988 and has performed 16 SLTs and 2 DLTs. Eight patients with emphysema had satisfactory results following SLT, and 13 of 16 SLT and both DLT patients are alive and well.

Transplantation Society (January 1991) states that LT is no longer an experimental procedure and should be regarded as a reimbursable service when performed at centers with personnel having expertise acknowledged by their peers.

Cystic Fibrosis Foundation (February 1991) states that CF is now the second most common indication for DLT (which will most likely replace HLT as the treatment of choice for end-stage patients with this disease). Seven DLT centers in the United States have performed 23 DLTs; 18 of these patients are surviving (78), the longest now surpassing 5 years. Experience in France indicates 11 of 16 patients surviving DLT for CF.

Walter Reed Army Medical Center (April 1991) states that both SLT and DLT are proven and accepted life-saving options for selected patients with end-stage pulmonary disease.

University of Maryland School of Medicine, Department of Surgery (April 1991) includes COPD, CF, pulmonary fibrosis, pulmonary hypertension, and Eisenmenger's syndrome as indications for LT and states that there are no absolute contraindications for LT.

American College of Cardiology (April 1991) states the SLT or DLT is appropriate therapy for patients with end-stage primary lung disease who have mild or absent right ventricular dysfunction.

Yale University School of Medicine (May 1991) states that LT has become an accepted therapeutic option for selected patients with end-stage pulmonary disease. Candidates for LT should be younger than 50, without extensive prior chest surgery, infection, or other organ system failure, and should have no contraindications related to immunosuppression.

United Network for Organ Sharing (June 1991) states that the techniques of SLT and DLT have been perfected and successfully applied to patients with septic lung disease and particularly in patients with CF. In addition, they list the following general medical indications for LT: idiopathic or acquired interstitial pulmonary fibrosis; severe obstructive pulmonary disease, including emphysema and asthma; AAT deficiency; primary pulmonary hypertension; bronchiolitis obliterans; CF; congenital or acquired bronchopulmonary dysplasia; and congenital malformations with pulmonary hypoplasia or dysplasia, including congenital diaphragmatic hernia, congenital adenomatoid malformation, and certain cases of congenital lobar emphysema.

Institutional resources required for an LT program should include:

  1. A lung transplant team with expertise in complex thoracic surgical problems; individuals having prior experience with clinical LT are desirable.
  2. A pulmonary medicine section with individuals who have expertise in managing chronic lung disease and in pulmonary rehabilitation; an institutional program in pulmonary rehabilitation and in prevention of chronic lung disease is desirable.
  3. Institutional experience with solid organ transplantation in general is essential; this implies the presence and active participation of experts in infections disease, clinical immunology, and psychiatry and an appropriate nursing unit for the care of lung transplant recipients.
  4. Staff with experience in complex cardiac surgery; the presence of staff with experience in cardiac transplantation or cardiopulmonary transplantation is desirable.
  5. An intensive care unit with expertise in managing postoperative general thoracic surgical patients, including immunosuppressed patients and their pulmonary problems; the capability for extracorporeal membrane oxygenation treatments is desirable.
  6. At least two clinically experienced thoracic anesthesiologists assigned to the lung transplant program.

Summary

Lung transplantation currently involves the allografting of one or both lungs from a cadaver or brain-dead donor to selected patients with progressive end-stage pulmonary disease for whom there are no other viable treatment options.

Expanding experience since 1986 in Canada, the United States, and Europe has demonstrated that both SLT and DLT can provide adequate pulmonary function and palliation for extended periods in some patients with otherwise fatal lung disease. A more rapid expansion of this technology has been constrained by the scarcity of suitable donors and the current limits of organ preservation time. Lung transplantation have evolved as a clinical procedure achieving a favorable risk-benefit ratio and acceptable 1-and 2-year survival rates.

Lung transplantation is applied as a therapeutic option for patients with end-stage pulmonary disease. However, the transplant community has not yet reached consensus regarding patient selection criteria or absolute contraindications to LT. Specific selection criteria for the optimal treatment of all LT candidates do not exist as yet and are currently evolving. The majority of candidates have had pulmonary fibrosis, bronchiectasis, emphysema, pulmonary hypertension, or CF.

Additional clinical information and experience will be useful in refining evaluation of risk-benefit ratios of SLT and DLT, which may vary for specific subsets of patients.

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