EJCTS Click here for details of sales representative
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Eur J Cardiothorac Surg 2008;34:444-448. doi:10.1016/j.ejcts.2008.03.068
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Benjamin Medalion
Milton Saute
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shitrit, D.
Right arrow Articles by Kramer, M. R.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Shitrit, D.
Right arrow Articles by Kramer, M. R.
Related Collections
Right arrow Lung - cancer
Right arrow Lung - other
Right arrow Lung - transplantation

Risk factors for death while awaiting lung transplantation in Israeli patients: 1997–2006

David Shitrita,c, Yvgeni Gershmanc, Nir Peleda,c, Benjamin Medalionb,c, Milton Sauteb,c, Anat Amitala, Mordechai R. Kramera,c,*

a Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel
b Cardiothoracic Department, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel
c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Received 17 October 2007; received in revised form 29 February 2008; accepted 6 March 2008.

* Corresponding author. Tel.: +972 3 9377221; fax: +972 3 9377142. (Email: davids3{at}clalit.org.il).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
 References
 
Objective: Patients with end-stage lung disease very frequently die while awaiting lung transplantation. The aim of this study was to identify factors associated with mortality in patients referred for lung transplant assessment. Methods: The files of all consecutive patients listed for lung transplantation in Israel between 1997 and 2006 were reviewed and the data were compared statistically between those who survived to transplantation. Results: A total of 229 patients were listed for lung transplantation, of whom 42 (18.3%) died while awaiting transplantation. Comparison of the patients who survived to transplantation with those who did not using univariate analysis revealed that the died-waiting group was significantly older, used steroids to a greater extent, had more IPF patients and less emphysematous, and lower mean oxygen saturation at rest (p = 0.005). There were no between-group differences in comorbid diseases or pulmonary function measurements. The 6 min walk distance was strongly and inversely correlated with risk of death before transplantation (p = 0.005). On multivariate analysis, only oxygen saturation at rest was a significant independent risk factor for death while awaiting transplantation (OR 0.886; C.I. 0.805–0.974). Conclusions: There are several risk factors for death in the Israeli population listed for LTX, including age, steroid use, emphysematous patients and lower saturation at rest.

Abbreviations: LTX = lung transplantation • UNOS = United Network for Organ Sharing • 6MWD = six minute walk distance test • CPET = cardiopulmonary exercise test

Key Words: Lung transplantation: Waiting list: Emphysema • Pulmonary fibrosis • Mortality


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Comment
 References
 
Patients with end-stage lung disease very frequently die before an appropriate donor lung becomes available for transplantation. The reported waiting time for patients initially registered on the United Network for Organ Sharing (UNOS) lung transplant waiting list in 1996 was 567 days [1]. Traditionally, in the United States, available lungs were allocated to listed patients who matched the donor blood type and body size solely on the basis of accrued active waiting time. Recently, the policy was changed to take the medical urgency into account as well [1–4]. However, the specific factors that affect prognosis in this setting have not been extensively studied, and in the absence of knowledge on reliable predictors of death, prioritizing patients by medical urgency is impossible. Some of the initial studies addressing this issue found that poor survival before transplantation was associated with type of end-stage lung disease [5–7], especially pulmonary fibrosis, cystic fibrosis and primary pulmonary hypertension, in addition to male sex, older age, nonresponse to steroids (in patients with pulmonary fibrosis) and ABO blood type [5–7]. Others identified risk factors in subgroups of end-stage lung disease, including sarcoidosis and cystic fibrosis [8,9]. However, information on current estimates of survival among all listed lung transplant candidates remains sparse.

The aim of this study was to identify factors associated with mortality in patients referred for lung transplantation (LTX) assessment in Israeli population listed for LTX.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Comment
 References
 
2.1 Patients
We reviewed the records of all consecutive patients with end-stage lung disease assessed for LTX between January 1997 and May 2006 at Rabin Medical Center, the only referral facility for LTX in Israel. The patients had been screened and evaluated for transplantation while clinically stable, using standard criteria [10,11], and all were followed for at least 6 months.

The study was approved by the ethics committee of Rabin Medical Center.

2.2 Procedure
The data collected during evaluation for transplantation were as follows: age, sex, height, and weight; medical history, including type of end-stage lung disease, time since diagnosis of end-stage lung disease, steroid use, smoking status, and comorbid diseases; blood biochemistry parameters, pulmonary function, arterial blood gas levels, distance on the 6 min walk test, and findings on cardiopulmonary exercise test and cardiac catheterization.

The eligible candidates for lung transplantation were registered on the waiting list of the Israel National Transplant Center. Routine medical management was continued during the waiting period under the supervision of the medical team. Organs were allocated to listed patients who matched the blood type and body size of the donors according to accrued active time on the list.

2.3 Study variables
For purposes of the study, the demographic, clinical and laboratory data of all listed patients were retrieved from the files, and their status at the end of the study period was documented as follows: survived to transplantation or died while awaiting transplantation. All patient deaths were corroborated against the records of the Israel National Transplant Center.

2.4 Data analysis
Results are shown as mean ± standard deviation. Pearson correlation coefficient (r) and the significance for it (p) were calculated between the variables. To analyze differences in the distribution of categorical data, chi-square test or Fisher's exact test was used, as appropriate. Differences in mean continuous variables between two groups of patients by status at the end of the study were analyzed by t-test. The data were fitted to a logistic regression model to identify predictors of death. Odds ratios and 95% confidence intervals were calculated from the model. A p value of 0.05 or less was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Comment
 References
 
During the study period, 229 patients were listed for LTX, of whom 42 (18.3%) died while awaiting transplantation. Of the remainder, 125 patients underwent single LTX, 14 underwent heart–lung transplantation, and 28 underwent double LTX.

Mean time to transplantation in the survivors was 9.6 ± 9.4 months.

The patient characteristics are presented in Tables 1 and 2 . Comparison of the patients by status at the end of the study period yielded several significant differences by a univariate analysis. The patients who died while awaiting transplantation were older than those who survived to transplantation (55 ± 13 years vs 49 ± 14 years, p = 0.01), used steroids to a greater degree (14 ± 15 mg/day vs 9 ± 13 mg/day, p = 0.02) and smoked more (p = 0.04). Comorbid diseases were similar in the two groups, including hypertension, diabetes mellitus, osteoporosis, and ischemic heart disease. No differences were noted in pulmonary function measurements. The died-waiting group had a significantly lower albumin level (3.8 ± 0.4 g/dl vs 4.0 ± 0.4 g/dl, p = 0.008) and significantly higher lactate dehydrogenase level (525 ± 199 u/l vs 450 ± 174 u/l, p = 0.02). The only cardiopulmonary parameter that was significantly different between the groups was oxygen saturation at rest (91 ± 8% vs 94 ± 4%, p = 0.005). The 6 min walk distance was strongly and inversely correlated with risk of death before transplantation (270 ± 80 m vs 358 ± 108 m, p = 0.005). The hemodynamic profile and the catheterization findings were similar in the two groups.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline characteristics of the study population at evaluation for transplantation by patient status at the end of the study
 

View this table:
[in this window]
[in a new window]

  		Table 2 Cardiopulmonary features of patients at evaluation for transplantation by status at end of study period
 
In the Cox proportional hazards model, only oxygen saturation at rest emerged as a significant independent risk factor for death while awaiting LTX with OR = 0.886 (C.I. 0.805–0.974) (Figs. 1 and 2 ).


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 1. Six min walk distance values of patients who died while awaiting transplantation (n = 42) versus patients who survived to transplantation (n = 187), p = 0.005.

 

Figure 2
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 2. Saturation at rest of patients who died while awaiting transplantation (n = 42) versus patients who survived to transplantation (n = 187), p = 0.005.

 

   4. Comment
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
References
 
Lung transplantation is an acceptable mode of therapy for patients with end-stage lung disease. However, there is a severe shortage of suitable donor lungs, and in the last 5 years, approximately 2500 potential lung recipients have died while on the UNOS lung transplant waiting list [12]. The discrepancy between the supply and demand for organs has resulted in intense scrutiny of organ distribution systems [3,13] and a search for factors indicating medical urgency.

Mannes et al. [14] showed that the type of end-stage lung disease might impact on patients’ chances of surviving the LTX. While patients with pulmonary fibrosis and emphysema had an equally high probability of transplantation, patients with emphysema were less likely to die while on the waiting list. These findings supported the data of the UNOS registry [1] and those of Kerem et al. [15], who reported the lowest mortality rate in transplant candidates with emphysema and the highest in candidates with pulmonary hypertension (29.6%) or cystic fibrosis (36.8%).

Our study yielded similar findings, with statistically significant differences between the survivors to transplantation and the died-waiting group (Table 1).

Studies of specific potential risk factors of death while awaiting LTX in patients with cystic fibrosis [8,15,16] reported significant findings for short distance on the 6 min walk test, high pulmonary artery pressure, and presence of diabetes mellitus. By contrast, in a landmark study, Kerem et al. [15] found that a low forced expiratory volume in one second (FEV1) (below 30% of predicted) was the most significant risk factor for death in this patient subgroup. In patients with end-stage sarcoidosis, Shorr et al. [16], in a large study of 405 LTX candidates, found race, pulmonary hypertension and oxygen saturation to be the most important risk factors.

The new algorithm for lung allocation to listed patients, adopted in 2005, involves the calculation of a lung allocation score (LAS) for each candidate which takes the following variables into account: forced vital capacity, pulmonary arterial systolic pressure, supplemental oxygen required at rest, age, body mass index, presence of insulin-dependent diabetes, functional status, 6 min walk distance, pulmonary capillary wedge pressure, creatinine level, and diagnosis [17]. In addition, the analysis is repeated every 6 months to ensure that the algorithm remains dynamic and is properly adapted to the currently listed population. However, the system has two main disadvantages: it is complex and difficult to understand by both patients and transplant professionals [3], and it has not undergone either internal or external validation, making its present implementation questionable.

Our study was conducted in Israel, where the new model has not yet been adopted and the only criteria for organ allocation (beside blood type and body size) are the accrued active time on the list. In addition, the current program gives the priorities also to the type of transplantation (first to single lung, double lung and only after that to heart–lung transplantation).

In Israel 10% of the patients waiting for LTX had cystic fibrosis (CF) and 4% had PPH, respectively (Table 1). The high rate of HLT in the study population is due to the fact that heart-lung transplantation (HLT) is the preferred surgery to Eisenmenger disease as well as primary pulmonary hypertension (PPH). Patients with severe heart failure and lung disease also underwent HLT (n = 5).

Using a retrospective design, we sought to identify factors associated with improved survival on the waiting list in patients referred for LTX assessment. These including several clinical parameters (low age, diagnosis of emphysema, low rate of smoking status, lower dose of steroid; Table 1), laboratory parameters (high albumin and low lactate dehydrogenase levels; Table 2), and lung function parameters (longer 6 min walk distance and higher oxygen saturation; Table 2 and multivariate analysis). However, only oxygen saturation at rest proved to be a significant independent predictor of survival to LTX.

Interestingly, our results were not significant for high pulmonary arterial pressure, a known risk factor for death in listed patients [5–7]. One explanation for this discrepancy could be the low pulmonary arterial pressure in our patients (Table 2). The 6 min walk distance test integrates cardiopulmonary function, strength, and endurance, and it has been proposed as a useful guide in the decision to list patients for transplantation [8]. In our analysis, the risk of death decreased noticeably with an increase in the 6 min walk distance.

Our study has a several potential shortcomings. Errors could have been introduced during the retrospective data collection, although various techniques were used to minimize them. To lower the chances of omitting pertinent variables, we reviewed all parameters that have shown prognostic importance in previous studies and carefully recorded all relevant data from the patients’ evaluations. Missing data, too, could have been a source of bias. However, the amount of missing information was small, and the pattern was not very different between the two groups. In addition, statistical adjustments for missing data did not significantly alter our findings. It should be noticed also that only one lung transplant group exists in Israel and thereby there is no competing national organs allocation policy. Finally, although the large number of variables analyzed increased the possibility that one of them could reach statistical significance by chance alone, we limited the set of variables in the Cox multivariate analysis by strict p values and by a priori hypotheses.

On the basis of the findings of the present study, we concluded that in the Israeli population listed for LTX severe hypoxemia, pulmonary fibrosis, high steroid usage, and poor 6MWD are predicted for poor prognosis.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Comment
 References
 

  1. Organ Procurement and Transplantation Network; final rule. CFR Part 121. Federal Register 63 (No. 63):16296–16338; 1998.
  2. Organ Procurement and Transplantation Network; final rule. 42 CFR Part 121. Federal Register 64 (No. 202):16296–16338; 1999.
  3. Egan TM, Kotloff RM. Pro/Con debate: Lung allocation should be based on medical urgency and transplant survival and not on waiting time. Chest 2005;128:407-415.[CrossRef][Medline]
  4. Quwens JP, Groen H, TenVergert EM, National Steering Group for Lung Transplantation Simulated waiting list prioritization for equitable allocation of donor lungs. J Heart Lung Transplant 2002;21:797-803.[CrossRef][Medline]
  5. Tukiainen P, Taskinen E, Holsti P. Prognosis of cryptogenic fibrosing alveolitis. Thorax 1983;38:349-355.[Abstract/Free Full Text]
  6. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 1980;35:171-180.[Abstract/Free Full Text]
  7. Gay SE, Kazerooni EA, Toews GB. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1994;149:1583-1590.[Abstract]
  8. Vissa CD, Yusen RD, Lynch JP. Outcome of patients with cystic fibrosis awaiting lung transplantation. Am J Respir Crit Care Med 2000;162:819-825.[Abstract/Free Full Text]
  9. Timmer SJ, Karamzadeh AM, Yung GL. Predicting survival of lung transplantation candidates with idiopathic interstitial pneumonia. Chest 2002;122:779-784.[CrossRef][Medline]
  10. ASTP/ATS/ERS/ISHLT. International guidelines for the selection of lung transplant candidates. Joint statement of the American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT). Am J Respir Crit Care Med 1998;158:335–9.
  11. Trulock EP. Lung transplantation. State of the art. Am J Respir Crit Care Med 1997;155:789-818.[Medline]
  12. U.S. Organ Procurement and Transplantation Network and The Scientific Registry of Transplant Recipients. 2003 Annual Report. Rockville, MD/Richmond, VA: U.S. Department of health and Human Service/Health Resources and Services Administration [HHS/HRSA/United Network for organ Sharing (UNOS)]; 2004.
  13. Meester JD, Smits JMA, Persijin GG, Haverich A. Lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration. J Heart Lung Transplant 1999;18:563-571.[CrossRef][Medline]
  14. Mannes GP, de Boer WJ, van der Bij W. Three hundred patients referred for lung transplantation. Experiences of the Dutch lung transplantation program. Groningen Lung Transplantation Group. Chest 1996;109:408-413.[CrossRef][Medline]
  15. Kerem E, Reisman J, Corey M. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;327:1244-1245.[Medline]
  16. Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung transplantation. Chest 2003;124:922-928.[CrossRef][Medline]
  17. Mogulkoc N, Brutsche MH, Bishop PW. Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med 2001;164:103-108.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 ThoraxHome page
T J Corte, S J Wort, M A Gatzoulis, P Macdonald, D M Hansell, and A U Wells
Pulmonary vascular resistance predicts early mortality in patients with diffuse fibrotic lung disease and suspected pulmonary hypertension
Thorax, October 1, 2009; 64(10): 883 - 888.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Benjamin Medalion
Milton Saute
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shitrit, D.
Right arrow Articles by Kramer, M. R.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Shitrit, D.
Right arrow Articles by Kramer, M. R.
Related Collections
Right arrow Lung - cancer
Right arrow Lung - other
Right arrow Lung - transplantation

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS