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Keywords:

  • Body weight;
  • female;
  • lung transplantation;
  • quality of life

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

A fundamental goal of lung transplantation is the regaining of functional capacity, yet little is known about what factors are associated with the achievement of this goal. The aim of this study is to test the association of clinical risk factors with functional status 1 year following lung transplantation. We conducted a cohort study of 321 lung transplants and assessed functionality by the distance achieved during a standard 6-min walk test (6MWT). Preoperative recipient risk factors were evaluated for association with functional status and adjusted for confounding using multivariable linear regression models. In these multivariable analyses, recipient female gender (p < 0.001), recipient pretransplant body mass index (BMI) of greater than 27 kg/m2 (p = 0.017) and shorter pretransplant 6MWT distances (p = 0.006) were independently associated with shorter distances achieved during 6MWT after lung transplant, while cystic fibrosis (CF) (p = 0.003), and bilateral lung transplant (p = 0.014) were independently associated with longer distances achieved. Approximately 51% of the variance in 6MWT distance was explained by these risk factors in the linear regression models (R2= 0.51). These findings may have implications in patient counseling, selection, procedure choice, and may lead to interventions aimed at improving the functional outcomes of lung transplantation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Lung transplantation is an intervention that offers patients with advanced lung disease the possibility of extended survival, improved quality of life (QOL) and functional independence (1). However, significant constraints on long-term outcomes remain, as evidenced by 5- and 10-year survival rates of only 47% and 24%, respectively (2). Indeed, whether transplantation actually confers a dramatic survival advantage over the natural history of some advanced lung diseases remains unclear. While some studies suggest such a benefit (3,4), others call this into question, particularly in patients with emphysema, cystic fibrosis (CF) and Eisenmenger syndrome (3,5,6). In reality, many patients are motivated to pursue transplantation in the hopes of realizing a dramatic improvement in their QOL. The ability to perform activities of daily living, return to social activities and lead productive lives are regarded by most patients as essential goals that influence the eventual decision to undergo lung transplantation.

There is growing interest in determining the impact of lung transplantation on functional status and QOL in patients with advanced lung disease (7–9). Preliminary studies employing standardized QOL questionnaires have reported significant short- and intermediate-term improvements in various QOL measures following lung transplantation (10–12). However, due to the many complications that can ensue following transplantation, not all patients achieve a functionally successful outcome. To date, there are no studies specifically examining risk factors for poorer functional outcomes following lung transplantation.

The goal of this study is to test the association of clinical risk factors with 1-year functional status in a cohort of lung transplant recipients. Our study hypothesis is that recipient, donor and surgical variables present at or prior to the transplant procedure are associated with poorer functional outcome. To test this hypothesis, we have defined functional outcome by the distance achieved following a 6-min walk test (6MWT) within the first posttransplant year.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population

This retrospective cohort study was performed on all the 321 consecutive lung transplant recipients at the University of Pennsylvania Medical Center between November 1991 and August 2001, with 1-year follow-up time. One heart–lung transplant patient and two lung–liver transplant patients were excluded from analysis. This protocol was approved by the Institutional Review Board of the Office of Regulatory Affairs at the University of Pennsylvania.

Definition of primary outcome

The primary outcome measure of this study was the maximum distance achieved during a standard 6MWT during the first year following lung transplantation. We did not restrict the collection of outcome data to a single time point at 12 months, because we felt that recipients who achieved a normal 6MWT distance at 3–6 months per se should be counted as achieving good functional status, even if they developed a subsequent event that influenced 6MWT distance at the 12-month mark. In addition, use of the maximal 6MWT distance from the first year would avoid capturing a single poor test result that may have occurred due to a concurrent illness. For example, if a patient developed acute rejection a few weeks prior to scheduled testing at the 12-month mark, then this single test result may not be reflective of best 6MWT distance during the first year following lung transplantation, and would bias the outcome. The 6MWT was conducted according to a standardized protocol using an internal hallway with 100-feet distance marked on the floor (14). The standardized protocol includes providing supplemental oxygen therapy should the oxyhemoglobin saturation by pulse-oximetry drop below 90% during the test.

The 6MWT provides a standardized, objective, integrated measure of the cardiopulmonary and musculoskeletal system that is relevant to activities of daily living (13). Studies evaluating outcomes in cardiopulmonary disease have often used the 6MWT as the gold standard for criterion validity (14–17); and other studies have established the 6MWT distance as a reliable and valid measure of functional capacity (18–20). The significance of small differences in the distance of the 6MWT may be unclear. Differences of 177 feet (95% confidence interval: 121 to 232 feet) are described as clinically significant in chronic obstructive pulmonary disease patients (21,22).

Standard transplant protocol

The transplant protocol for our center has been previously published (including donor selection, surgical technique, immunosuppression and postoperative management) (23). All patients in this cohort study underwent a 6MWT before and after lung transplantation.

Bilateral lung transplantation was performed in all recipients with suppurative lung disease and in the majority of recipients with pulmonary hypertension. The decision to perform bilateral versus single lung transplant in other recipient diagnoses were largely individualized and typically reserved for younger recipients (less than 60 years of age) and recipients without contraindication for bilateral procedures such as prior pleurodesis.

Recipients at our program are strongly encouraged to enroll in a pretransplant pulmonary rehabilitation program in their local community, however all posttransplant recipients are mandated to participate in a 3-month, 3 days per week standardized pulmonary rehabilitation at the Hospital of the University of Pennsylvania. This program typically includes performance on a treadmill, stationary bike and use of free weights. Insurance clearance for this rehabilitation program is obtained prior to listing and is mandatory in order to be listed for lung transplant.

Risk factor variables tested for association with functional status

Clinical risk factors were selected based on hypothesized associations with functional status. We focused on pretransplant risk factors to be able to identify areas for potential counseling and pretransplant modification. Risk factors included recipient age, race, gender, pretransplant diagnosis, transplant type, cytomegalovirus (CMV) serology status, recipient weight, smoking history, marital status, use of anti-depression medication, education level and use of cardio-pulmonary bypass for the surgery. Race data were collected according to the specific National Institute of Health race classification (24) and then categorized as Caucasian, African-American or other. Pretransplant diagnoses were categorized as follows: (1) obstructive pulmonary diseases including emphysema, chronic bronchitis, bronchiectasis, bronchiolitis, lymphangioleiomyomatosis; (2) pulmonary vascular diseases including idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension secondary to congenital heart diseases; (3) CF; and (4) interstitial lung diseases including idiopathic pulmonary fibrosis and sarcoidosis.

Recipient age was assessed as a continuous variable. Due to the potential for age having a nonlinear association with 6MWT distance, age data were also divided into quartiles. Weight was assessed at the time of transplant evaluation using body mass index (BMI) in kilograms divided by height in meters, squared (25). Due to the potential nonlinear distribution of the BMI variable, we evaluated BMI using quartiles. One-year posttransplant BMI data in survivors were evaluated for association with 6MWT distance. Smoking history was a dichotomous variable, where ‘yes’ indicated more than a 10-pack year tobacco exposure and ‘no’ represented lifelong nonsmoker or less than 10-pack year tobacco exposure. No data on ‘current’ smokers are available because current smoking is an exclusion criterion to receiving a lung transplant. Similarly, depression medications were treated as a dichotomous variable with ‘yes’ indicating use of any antidepressant medication at time of evaluation and ‘no’ represented no use of the medication. The marital status variable consisted of two categories; (1) ever married and (2) single. Education was categorized as having obtained at least the following: (1) high school, (2) college degree and (3) other. Cytomegalovirus serology status was also recorded as a dichotomous variable with recipients being either CMV serology positive or CMV serology negative at the time of evaluation.

The two major types of lung transplantation procedures are single and bilateral lung transplants. All bilateral lung transplants in this study population were bilateral sequential lung transplants. The use of cardio-pulmonary bypass was also assessed at the time of surgery. One-year posttransplant pulmonary function data were evaluated for association with 6MWT distance.

When choosing our variables, we did not specifically include height, since it is a component of the BMI calculation, and thus is highly collinear. In addition, we adjusted for individual pretransplant 6MWT distance and we adjusted for height when calculating age-appropriate 6MWT distance in the logistic regression models. Therefore, we have not included height as a separate variable in the linear regression model.

Data collection

Data were collected from review of pre-existing medical records. A specific structured chart abstraction instrument was designed for data collection. The data for the primary outcome variable, 6MWT, were collected from review of the records from the pulmonary exercise laboratory at the University of Pennsylvania. Risk factor data were obtained from review of the transplant medical charts, an existing research database and electronic medical records available at the University of Pennsylvania Medical Center. Six-min walk test data were collected prior to and independent of the collection of candidate risk factor data in the study.

Analysis

Descriptive statistics including means, medians, ranges and standard deviations were examined. Categorical variables such as recipient gender and recipient diagnosis are reported as percentages, and continuous variables such as 6MWT distance are presented as means and standard deviations. The χ2 test or Fisher's exact test were used in comparisons of categorical variables, while the Student's t-test for continuous, normal data or by rank-sum test for noncontinuous and/or non-normal data after the distribution of the data was assessed for normality. Confidence intervals (95% CI) and tests of significance were calculated using standard approaches (26).

Multiple linear regression analyses were performed to determine the association between distance walked during the 6MWT and potential risk factors. Each candidate risk factor was first correlated with the distance achieved during the 6MWT, and variables were selected for inclusion in the multivariable explanatory analysis if they exhibited significance at an α of <0.20 (27,28). We added variables into the multiple linear regression model starting with the lowest p-value variables and then proceeding to the highest p-value variables. The purpose of the multivariable analysis was to test the association of each risk factor with 6MWT distance achieved, while adjusting for other variables. Potential confounding variables were added to the regression equation containing the risk factor variable of interest one at a time. A summary-adjusted model was created containing all variables that changed the coefficient of the risk factor of interest by more than 15% with adjustment. A p-value < 0.05 following adjustment for all confounding variables was considered significant.

Following adjustment for confounding, we sought to assess the explanatory impact of postoperative pulmonary function on 6MWT distance as a potential causal pathway variable (29). Since pulmonary function measured at 1 year following transplant is an integral part of functional status, we added forced expiratory volume in 1 second (FEV1) at 1 year to the final model to assess explanatory effect on the relationship of our final risk factors with 6MWT.

To address potential bias introduced by varying times of performance of the 6MWT, we performed a secondary linear analysis limiting the cohort to recipients whose testing only occurred at the 1 year anniversary (±30 days). To avoid the issue of collinearity regarding CF recipients and bilateral lung transplantation, we performed a secondary linear regression analysis and excluded the CF recipients from this analysis.

In addition to the multiple linear regression analysis described above, we also performed a complimentary logistic regression analysis by assessing functional status by the ability to achieve or not to achieve a normal minimum age-appropriate 6MWT distance within 1 year following lung transplantation. We compared whether or not the patients best-achieved distance met the minimum age-appropriate 6MWT distance defined by standards in normal subjects (30,31). This test is gender specific with different reference values given for men and women. The same risk factors variables used in the linear model were assessed in this dichotomous model.

Early mortality

Death within 1 year following lung transplantation may potentially compete for the primary outcome of interest by censoring subjects prior to their having the ability to potentially achieve the outcome. This type of censoring may occur, for example, if recipients with interstitial lung disease have a greater ability to achieve a greater 6MWT distance if they survive, but these patients also experience higher 1-year mortality. In this case, by selecting out only the survivors who are likely the strongest, it may appear that interstitial lung disease recipients have better functional outcomes. To deal with this potential competing effect, we created a separate logistic regression model with the dichotomous definition of achieving a normal 6MWT distance, which assumed death within 1 year to be included as ‘poor functional status’ and we refit the univariate and multivariable models. We then compared the models to see if the effects on the variables were different. All statistical comparisons were performed using STATA version 8.0 (STATA Corporation; College Station, TX, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Of the 321 study-eligible patients, 91 patients died within 1 year following lung transplantation. Two hundred and forty-eight 6MWTs were performed within 1 year following lung transplant. Twenty-three of these tests were performed in recipients who died within 1 year. Details of the cohort study population are included in Figure 1. In the whole population, the mean 6MWT distance walked pretransplant was 1000 feet (SD ± 342) and the mean maximum 6MWT distance in the first year posttransplant was 1544 feet (SD ± 448). The lowest mean oxyhemoglobin saturation during the pretransplant 6MWT was 91% (SD ± 4.8) and the lowest mean oxyhemoglobin saturation posttransplant 6MWT was 96% (SD ± 3.4). A description of the candidate risk factors by 1-year survival are presented in Table 1.

image

Figure 1. Lung transplant cohort outcome (6MWT = 6-min walk test).

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Table 1.  Description of candidate risk factors in survivors and nonsurvivors*
VariablesSurvived 1 year following lung transplant group (n = 227)Nonsurvivor group (n = 91)p-value
  1. *Data are presented as no. of patients/total (%) or mean ± SD unless otherwise indicated.

6-min walk distance pretransplant (feet)1031.5 ± 343.7931.6 ± 332.90.026
6-min walk distance 1 year posttransplant (feet)1598 ± 409.71025.3 ± 480.6<0.001
Age (years)49.1 ± 11.252.2 ± 9.20.87
Gender:
 Male117 (52)46 (51)Referent
 Female110 (48)45 (49)0.873
Race:
 Caucasian203 (89)83 (91)Referent
 African-American19 (9)7 (8)0.82
 Other5 (2)1 (1)0.52
Recipient diagnosis:
 Obstructive lung disease156 (69)49 (54)Referent
 Pulmonary vascular disease15 (7)15 (17)0.004
 Cystic fibrosis22 (9)7 (7)0.98
 Interstitial lung disease34 (15)20 (22)0.054
 Pretransplant BMI (kg/m2)23.9 ± 4.524 ± 4.70.88
 Posttransplant BMI (kg/m2)26 ± 4.9N/A 
Recipient smoking history:
 Positive smoking history182 (81)70 (78)Referent
 Negative smoking history43 (19)20 (22)0.53
Use of antidepressants at evaluation:
 Use of antidepressants73 (33)26 (29)Referent
 No use of antidepressants149 (67)65 (71)0.46
Marital status:
 Single33 (17)11 (14)Referent
 Married156 (83)66 (86)0.53
Education level: 0.33
 High school130 (65)54 (63)Referent
 College54 (27)19 (22)0.6
 Graduate15 (8)13 (15)0.07
Recipient cytomegalovirus serology:
 CMV negative93 (41)34 (38)Referent
 CMV positive133 (59)56 (62)0.58
Transplant type:
 Single lung transplantation123 (54)50 (55)Referent
 Bilateral lung transplantation104 (46)41 (45)0.9
Use of cardio-pulmonary bypass at the time of surgery:
 No175 (77)60 (66)Referent
 Yes52 (23)31 (34)0.041
Single lung transplant:
 Posttransplant FEV1 (actual)1.68 ± 0.5N/A 
 Posttransplant FEV1 (% predicted)57 ± 16N/A 
 Posttransplant forced vital capacity (FVC) (actual)2.55 ± 0.7N/A 
 Posttransplant FVC (% predicted)69 ± 15N/A 
Bilateral lung transplant: N/A 
 Posttransplant FEV1 (actual)2.75 ± 0.9N/A 
 Posttransplant FEV1 (% predicted)85 ± 25N/A 
 Posttransplant FVC (actual)3.41 ± 0.9N/A 
 Posttransplant FVC (% predicted)87 ± 20N/A 

Association of candidate risk factors with functional status

The results of the univariate analysis of risk factors associated with 6MWT distance are presented in Table 2. Female gender was associated with significantly lower 6MWT distance following lung transplantation (regression coefficient 260.5; 95% CI, 151 to 369; p-value < 0.001). Due to the nonlinear relationship of recipient age with the primary outcome, we initially assessed age as quartiles (Table 2), and then we reduced quartiles of age to three categories because the third and fourth age quartiles appeared to have similar coefficients with the outcome of interest. Older age was significantly associated with shorter distance achieved during the 6MWT (for example, recipients aged > 60 years achieved on average 318 feet less distance than recipients aged 18 to 45 years). Shorter pretransplant 6MWT distance (regression coefficient 0.46; 95% CI 0.28 to 0.64; p-value < 0.001) and use of cardio-pulmonary bypass at time of surgery (regression coefficient –145.9; 95% CI, −280 to −11; p-value = 0.03) were also associated with shorter 6MWT distances. Pretransplant diagnosis of CF was associated with better functional status as measured by the distanced achieved during a 6MWT when compared to obstructive lung disease (median 2146; range 1208 to 2722; p-value < 0.001). Survivors to at least 1 year following lung transplant (regression coefficient 572; 95% CI, 393 to 752; p-value < 0.001) and bilateral-type lung transplant (regression coefficient 275; 95% CI, 166 to 383; p-value < 0.001) were significantly associated with better functional status following lung transplant.

Table 2.  Univariate analysis of candidate risk factors associated with 6-min walk test distance (feet) performed within 1 year following lung transplantation*
Risk factor variablesCoefficient (SE)95% confidence intervalsp-value
  1. *Mean time from transplant to 6-min walk test was 332 days.

Age (years)49.1 ± 11.252.2 ± 9.20.07
Age strata (years):
 18–45ReferentReferentReferent
 46–53−230.7 (76)−380.7 to −80.60.003
 54–58−373.9 (77)−525.8 to −222<0.001
 59–65−376.3 (77)−528.8 to −223.8<0.001
 <50ReferentReferentReferent
 51–59−288.5 (60.2)−407 to −169.9<0.001
 >60−317.8 (86.7)−488.6 to −146.9<0.001
Gender:
 MaleReferentReferentReferent
 Female−260.5 (55)−369 to −151<0.001
Race:
 CaucasianReferentReferentReferent
 African-American8.1 (102)−193 to 2090.9
 Other337 (202)−61.5 to 736.40.09
Recipient diagnosis:
 Obstructive lung diseaseReferentReferentReferent
 Pulmonary vascular disease109 (105)−98.4 to 316.30.3
 Cystic fibrosis635 (93.8)450.6 to 820.1<0.001
 Interstitial lung disease63 (73.6)−81.8 to 2080.39
 Pretransplant BMI (kg/m2)−11.5 (6.5)−24.2 to 1.270.07
BMI strata (kg/m2):
 14.3–20.6ReferentReferentReferent
 20.7–23.5−74 (80)−232.5 to 840.36
 23.6–27.0−55.8 (82)−217.4 to 105.80.49
 27.1–38.1−182.1 (81)−342.3 to −21.90.02
 BMI less than/equal to 27ReferentReferentReferent
 BMI greater than 27−134.57 (65)−263 to −60.04
Recipient smoking history:
 Negative smoking historyReferentReferentReferent
 Positive smoking history−237.6 (72.3)−380 to −950.001
Use of antidepressants at evaluation:
 No use of antidepressantsReferentReferentReferent
 Use of antidepressants−75 (63)−200 to 480.23
Marital status:
 SingleReferentReferentReferent
 Married−219.3 (86.4)−389.8 to −490.012
Education level:
 High schoolReferentReferentReferent
 College119 (70)−20.6 to 2580.09
 Graduate64.1 (118)−169 to 2970.58
Recipient cytomegalovirus serology:
 CMV negativeReferentReferentReferent
 CMV positive−122.5 (58.5)−237.8 to −7.10.037
Transplant type:
 Single lung transplantationReferentReferentReferent
 Bilateral lung transplantation275 (55)166.4 to 383.6<0.001
6-min walk distance pretransplant (feet)0.46 (0.09)0.28 to 0.64<0.001
Survived to 1 year following transplant572.7 (91)392.9 to 752.6<0.001
Use of cardio-pulmonary bypass−145.9 (68)−280.4 to −11.40.03
Posttransplant BMI (kg/m2)−10.6 ± 8.1−26.5 to 5.40.20

The relationship of pretransplant BMI with the primary outcome did not appear linear, thus pretransplant BMI quartiles were established. The first, second, third and fourth quartile ranges were as follows: 14.3–20.6 kg/m2, 20.7–23.5 kg/m2, 23.6–27 kg/m2 and 27.1–38.1 kg/m2. Examining pretransplant BMI in quartiles, the fourth quartile, whose lowest value corresponded to a BMI value of 27 kg/m2, had dramatically different regression coefficient for the outcome of interest when compared to the other quartiles. As illustrated in Figure 2, no other quartile demonstrated such dramatic differences within or between quartiles. We used the lower bound of the fourth quartile (BMI = 27 kg/m2) value as a cut-off point since the 95% confidence intervals for the fourth quartile did not include 1. When treated as a dichotomous variable, pretransplant BMI greater than 27 kg/m2 was associated with poorer functional status (regression coefficient −135; 95% CI, −263 to −6; p-value = 0.04). One-year posttransplant BMI evaluated in a linear fashion or in quartiles did not appear to be significantly associated with 6MWT distance (regression coefficient −10.6; 95% CI, −26.5 to 5.4; p-value = 0.2) and therefore was not included in the multivariable analysis.

image

Figure 2. Pretransplant BMI cut-off point. Quartiles with squares represent the quartile mean and the bars represent the upper and lower values of the 95% confidence intervals.

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Based on the univariate analysis, the variables eligible to be included in the multivariable model were as follows: recipient gender, recipient age (three age categories), recipient diagnosis, pretransplant BMI greater than 27 kg/m2, survival to at least 1 year, pretransplant 6MWT distance, recipient smoking history, marital status, recipient CMV status, transplant type and use of cardio-pulmonary bypass. Using multivariable linear regression analysis, female gender (regression coefficient −220; 95% CI, −335 to −104; p-value < 0.001), pretransplant BMI greater than 27 kg/m2 (regression coefficient −165; 95% CI, −300 to −29; p-value = 0.017) and death within 1 year (regression coefficient −578; 95% CI, −756 to −400; p-value < 0.001) remained associated with poorer functional status after adjustment for age, pretransplant diagnosis, pretransplant 6MWT distance, recipient CMV status, use of cardio-pulmonary bypass, smoking history, marital status and transplant type. CF (regression coefficient 455; 95% CI 154 to 756; p-value = 0.003) and bilateral lung transplantation (regression coefficient 170; 95% CI 36 to 305; p-value = 0.014) are independently associated with better functional status following lung transplant. The adjusted regression coefficients for these variables in the final multivariable model are presented in Table 3. To address the issue of collinearity regarding CF recipients and bilateral lung transplantation, we performed a secondary linear regression analysis and excluded the CF recipients from this analysis. The association of the remaining clinical risk factors remained statistically unchanged in the absence of CF patients in the model.

Table 3.  Multivariable analysis of significant risk factors associated with 6-min walk test distance (feet) performed within 1 year following lung transplantation excluding posttransplant pulmonary function*
Risk factorsCoefficient (SE)95% confidence intervalsp-value
  1. *Adjusted for age, gender, pretransplant 6-min walk test distance, survival, recipient diagnosis, pretransplant BMI, recipient CMV status, transplant type, use of cardio-pulmonary bypass, recipient smoking history and recipient marital status.

  2. Model intercept: 632 feet.

Female gender−220 (58)−335.8 to −104.8<0.001
Pretransplant BMI >27 kg/m2−165 (68)−300.3 to −29.70.017
Pretransplant 6MWT distance0.26 (0.09)0.07 to 0.430.006
Survival578 (90)400.3 to 756.5<0.001
Cystic fibrosis455 (152)154.1 to 756.60.003
Bilateral lung transplant170 (68)35.5 to 305.20.014

The association of age and cardio-pulmonary bypass with poorer functional status lost statistical significance, as they were confounded by gender, transplant type and recipient diagnosis. Recipient smoking history, CMV status and marital status no longer were significant after adjustment for age, recipient diagnosis and transplant type in the multivariable model. The total amount of variance in 6MWT distance explained by the risk factors in the final model (R2) was 51%.

To assess the contribution of impaired pulmonary function on 6MWT distance, we included posttransplant FEV1 into the multivariable model, following all adjustment for confounding variables. When FEV1 at 1 year was added to the model, the association with female gender and pretransplant 6MWT distance remained significantly associated with poorer 6MWT distance (female gender regression coefficient −144; 95% CI −286 to −2.1; p-value = 0.04 and pretransplant 6MWT distance regression coefficient 0.6; 95% CI 0.31 to 0.8; p-value < 0.001). The associations of bilateral lung transplantation (regression coefficient −50; 95% CI −246 to 146; p-value = 0.61, CF (regression coefficient 266; 95% CI −84 to 618; p-value = 0.13) and pretransplant BMI (regression coefficient −86; 95% CI −227 to 53; p-value = 0.22) with 6MWT distance were no longer significant when adjusted for posttransplant FEV1 (Table 4), indicating that the relationship of these variables with 6MWT distance was at least partly explained by their effect on pulmonary function.

Table 4.  Multivariable analysis of significant risk factors associated with 6-min walk test distance (feet) performed within 1 year following lung transplantation including posttransplant pulmonary function*
Risk factorsCoefficient (SE)95% confidence intervalsp-value
  1. *Adjusted for 1-year posttransplant FEV1% predicted, age, gender, pretransplant 6-min walk test distance, survival, recipient diagnosis, pretransplant BMI, recipient CMV status, transplant type, use of cardio-pulmonary bypass, recipient smoking history and recipient marital status.

  2. Model intercept: 406 feet.

Female gender−144 (71)−286 to −20.04
Pretransplant BMI >27 kg/m2−86 (70)−227 to 540.22
Pretransplant 6MWT distance0.55 (0.12)0.3 to 0.79<0.001
SurvivalN/AN/AN/A
Cystic fibrosis266 (176)−84 to 6180.13
Bilateral lung transplant−50 (98)−246 to 1460.61
Posttransplant FEV1%6.8 (1.6)3.6 to 10<0.001

Fifty-nine percent of the posttransplant 6MWT performed in survivors occurred within 30 days of their 1-year transplant anniversary. When we restricted the analysis to include only these recipients (n = 133), the association of the same risk factors with 6MWT distance did not change, only the confidence intervals became wider as there were fewer subjects in the analysis (example: female gender regression coefficient 205.3; 95% CI, 91 to 410; p-value < 0.031)

To demonstrate the clinical impact, robustness and stability of these differences in 6MWT distance between our risk factors, we next performed complementary logistic regression analyses using the achievement of an age-appropriate 6MWT distance. Twenty-five percent (95% CI, 19.8 to 31.2) of recipients who survived 1 year did not achieve a normal age-appropriate 6MWT distance. The same clinical risk factors were associated with outcome in these analyses using the dichotomous outcome regarding ability to achieve a normal age-appropriate 6MWT distance. Female gender was associated with failure to achieve a normal age-appropriate 6MWT distance following lung transplantation (unadjusted odds ratio (OR), 3.49; 95% CI 1.83 to 6.65; p < 0.01). Thirty-seven percent of women versus 15% of men did not achieve a normal age-appropriate 6MWT distance. Although age is already adjusted for as part of the definition of the outcome, we felt it necessary to adjust for age to confirm that age did not confound the relationship with 6MWT distance in younger recipients. Relative to age less than 50 years, the odds of experiencing an outcome defined by failure to achieve a normal age-appropriate 6MWT distance 2.52 (95% CI, 1.27 to 4.99) for recipient age 51–60 years and 1.49 (95% CI, 0.59 to 3.75) for recipient age greater than 60 years. Pretransplant diagnosis of interstitial lung disease (ILD) and CF were both a greater likelihood of achieving the predicted 6MWT distance when compared to obstructive lung disease (unadjusted OR for not achieving expected 6MWT distance, 0.3; 95% CI, 0.1 to 0.9 for ILD and unadjusted OR for not achieving expected 6MWT distance, 0.1; 95% CI, 0.01 to 0.81) for CF.

Because the relationship of pretransplant BMI with the primary outcome did not appear linear, BMI quartiles were established as described earlier (Figure 2). When treated as a dichotomous variable, pretransplant BMI greater than 27 kg/m2 was associated with poorer functional status (unadjusted OR, 2.35; 95% CI, 1.25 to 4.43; p-value < 0.01).

To confirm the robustness of these results to the potential effects of early mortality, several logistic regression analyses were performed. The first logistic regression model included only those patients that survived to 1 year and the second logistic regression model included patients that died within 1 year of transplant as having a poor functional outcome. Table 5 presents a comparison of the results of the three multivariable models performed. Female gender, pretransplant BMI > 27 kg/m2, and shorter pretransplant 6MWT distance are independently associated with shorter posttransplant 6MWT distance even after evaluating posttransplant 6MWT distance as ever having achieved a normal age-appropriate 6MWT distance or not.

Table 5.  Comparison of the multivariable analysis models of the significant risk factors associated with 6-min walk test distance performed within 1 year following lung transplantation
Risk factorsLinear regression model* (p-values)Logistic regression model for survivors** (p-values)Logistic regression model including death as a poor outcome*** (p-values)
  1. *Adjusted for age, gender, pretransplant 6-min walk test distance, survival, recipient diagnosis, pretransplant BMI, recipient CMV status, transplant type, use of cardio-pulmonary bypass, recipient smoking history and recipient marital status.

  2. **Adjusted for age, gender, pretransplant 6-min walk test distance, recipient diagnosis, pretransplant BMI, recipient use on antidepressants and transplant type.

  3. ***Adjusted for age, gender, pretransplant 6-min walk test distance, survival, recipient diagnosis, pretransplant BMI and transplant type.

Female gender<0.0010.0030.003
BMI >27 kg/m20.0170.006<0.001
Pretransplant 6MWT distance0.0060.0070.01
Survival<0.001N/A<0.001
Cystic fibrosis0.0030.780.78
Bilateral lung transplant0.0140.280.04

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We have demonstrated that poorer functional status as measured by 6MWT distance following lung transplant was independently associated with female gender, a pretransplant BMI greater than 27 kg/m2 and shorter pretransplant 6MWT distance. In contrast, patients who survived 1 year, or who carried a pretransplant diagnosis of CF or underwent a bilateral lung transplant had better functional status following lung transplantation. The risk factors associated with poorer 6MWT distance were confirmed in several different analyses. In addition, we performed complementary analyses to demonstrate the robustness and stability of our risk factor association with 6MWT distance.

Female gender was strongly associated with poorer functional outcome. This finding is consistent with other studies that describe poorer functional status among women following other surgical procedures, such as coronary artery bypass graft surgery (32–34). The mechanism for the finding of worse functional outcomes in female recipients is unknown, but is independent of postoperative FEV1. Muscle wasting following lung transplantation can result from the catabolic stresses of surgery and high-dose corticosteroids. Females have less muscle mass than males so it is possible that they experience the adverse effects of muscle wasting more so than their male counterparts as it relates to functional capacity (35). In addition, calcineurin inhibitors are known to induce mitochondrial myopathy that may present with greater adverse functional effects in females than in males because of the differences in muscle mass (35–38).

Despite a narrow range of acceptable BMI considered for transplantation at our program (BMI greater than 18 kg/m2 and less than 30 kg/m2), we found that a pretransplant BMI of greater than 27 kg/m2 was associated with worse functional status than patients with lower BMI. This association with worse functional status remained robust even when patients who died within 1 year following lung transplantation were included. In support of our findings, Grady et al. reported that heart transplant recipients who were obese preoperatively had higher morbidity and mortality rates following transplantation (37). Studies within the lung transplant population have also reported that extremes of body weight can adversely impact outcomes (39). Our findings, together with these other studies, suggest that we need to be cautious in extending transplantation to those patients whose pretransplant BMI is greater than 27 kg/m2 and that among overweight patients, efforts should be made prior to transplantation to achieve a more suitable weight goal. In our study, posttransplant BMI measured at 1 year was not significantly associated with 6MWT distance. However, adjustment for postoperative FEV1 attenuated the relationship of pretransplant BMI with poor functional status, indicating that poorer pulmonary function mediated this effect at least in part.

In our study, a preoperative diagnosis of CF and bilateral lung transplant procedure were independently associated with better functional status following lung transplantation even when adjusting for age. We and others have previously demonstrated that bilateral lung transplantation is associated with longer 6MWT distance (40–42) but since recipients of the bilateral procedure are generally younger, these studies did not address whether superior functional outcomes were a procedure-related or age-related phenomenon. The current study is the first to adjust for age, and therefore demonstrate that the bilateral procedure itself is associated with superior functional outcomes. Furthermore, when we excluded CF subjects from the multivariable analyses, there was no change in the associations of remaining clinical variables with 6MWT distance. In addition, given that adjustment for postoperative pulmonary function attenuated this relationship, we conclude that the superior functional outcomes associated with the variables may be mediated by superior pulmonary function postoperatively.

We identified lower pretransplant 6MWT distance as a risk factor for inferior functional outcomes after lung transplantation. This observation would appear to justify intense efforts to address pretransplant debility and deconditioning by means of formal pulmonary rehabilitation. The mean difference between pre- and postlung transplant 6MWT distance was 544 feet. This is 2.5 times the upper limit of the 95% confidence interval found in the study by Redelmeier et al. who described a meaningful clinical difference of 177 feet (95% confidence interval: 121 to 232 feet) (21). The new American lung allocation system implemented by the United Network Organ Sharing (UNOS) (43) includes pretransplant 6MWT distance as one of the clinical variables used in calculating the lung allocation score. The current allocation model assigns a higher allocation score to candidates with 6MWT distances below 150 feet. Given our finding of an association between low pretransplant 6MWT distance and inferior posttransplant functional outcome, this aspect of the new lung allocation system warrants further scrutiny.

There were several variables of interest that did not have a significant relationship with poor functional status in our study. Age was evaluated as a categorical variable and although the relationship was statistically significant in the univariate analysis, when adjusted for transplant type, the relationship weakened considerably. Recipient smoking history, CMV status and marital status no longer were significant after adjustment for age, recipient diagnosis and transplant type in the multivariable model.

The total amount of variance in 6MWT distance explained by the final model (R2) was 51%. The remaining unexplained variability in 6MWT distance might be due to differences in muscle strength, physical activity of recipients and training level. These variables were not measured in our study.

Postoperative pulmonary function is an integral part of 6MWT performance, and can be thought of as a causal pathway variable. We conducted analyses that revealed that gender and pretransplant 6MWT distance had an impact on functional outcomes that was above and beyond the contribution of these variables to impaired pulmonary function. In contrast, pretransplant BMI, transplant type and diagnosis category seemed to have effects on functional status that was mediated through lower pulmonary function (29).

Our study has several potential limitations. First, it is a single-center study and may have limited generalizability to other transplant centers. Second, although our significant risk factors were adjusted for confounding effects of other variables, the potential for uncontrolled confounding exists. Potential confounders that we were unable to account for in the present study design include osteoporosis and other recipient factors such as employment status. We did not assess employment status due to potential information bias related to factors other than the outcome of interest (e.g. age and socioeconomic issues). Many patients remain on disability for medical insurance reasons and not reasons of functional incapacity. We could not assess osteoporosis due to the large amount of missing data within this variable; dual-energy x-ray absorptiometry was only routinely performed in the evaluation process toward the latter years of the transplant program and no data exist on the earlier transplanted patients.

Third, we have used the 6MWT as a measure of functional status to reflect functional aspects of QOL in patients undergoing lung transplantation. However, QOL is multifaceted and measurement of functional status reflects only one narrow component. A number of studies in lung transplant recipients (44) and adult respiratory distress syndrome (ARDS) survivors (45) have evaluated QOL and 6MWT and demonstrated correlation of the functional/physical domains of the QOL instrument with distance achieved during a 6MWT. Finally, although we had reasonable power to detect individual risk factors for functional status, some of our assessments of interaction between variables were limited by our sample size. Thus, we were unable to fully assess interaction between important risk factors.

We have identified several important risk factors that are associated with functional status following lung transplantation. Counseling regarding weight control may have a significant impact on outcomes following transplant and should be a focus of intervention for pretransplant readiness. Pretransplant pulmonary rehabilitation focused on improving distance walked by strength and endurance training is essential for favorable long-term functional outcome and will assist with pretransplant weight loss. Future investigations into the mechanism of inability to achieve longer 6MWT distances in female recipients and those with higher BMI are justified. On the other hand, bilateral lung transplantation and transplantation for CF recipients generally have excellent functional outcomes.

The full impact of the new organ allocation system is not yet known and the derived ‘net transplant benefit’ from this new allocation system is heavily influenced by 1-year mortality. Broadening this definition to include QOL measures and functional status may add additional utility to future organ allocation decisions.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Jeffrey S. Sager, M.D., M.S., was supported by a National Heart, Lung and Blood Institute Fellowship Training grant (T32 HL07891); Jason D. Christie, M.D., M.S., was supported by NHLBI K23 HL04243; Robert M. Kotloff, M.D., was supported by the Craig and Elaine Dobbin Pulmonary Research Fund of the University of Pennsylvania.

The authors are indebted to the nurse coordinators, physical therapists, respiratory therapists, counselors and the staff of Penn Transplant Center. Without their enthusiasm, diligence and skill, this study could never have been completed. We also want to thank Harold Feldman, M.D., M.S., and John Hansen-Flaschen, M.D., for their helpful discussion and suggestions.

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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