A Prospective Study Analyzing One-Year Multidimensional Outcomes in Living Lung Transplant Donors

Authors


Abstract

The success of living-donor lobar lung transplantation (LDLLT) largely depends on donor outcome; but to date, no authors have studied health-related quality of life (HRQOL) of donors. We prospectively evaluated multidimensional outcomes before and 1 year after donor lobectomies. Patient-reported HRQOL, dyspnea, psychological status and sleep quality, and physiological pulmonary function were determined. All donors were alive without any limitations in their activities of daily living after 1 year. Postoperative pulmonary function was better than the estimated preoperative values; but, with respect to HRQOL, four of the eight subscales of the Medical Outcomes Study 36-item short form (SF-36) deteriorated significantly after donation. In addition, dyspnea assessed by the modified Medical Research Council scale also worsened significantly. In contrast, postoperative anxiety assessed by the Hospital Anxiety and Depression Scale significantly improved from baseline. The donors whose recipients died reported lower SF-36 scores with worsening sleep quality measured by Pittsburgh Sleep Quality Index. Thus, although postoperative pulmonary functions in donors were preserved, their HRQOL and dyspnea deteriorated postoperatively. Moreover, HRQOL and sleep quality were impaired in recipients who experienced poor outcomes. To capture the comprehensive outcomes in LDLLT donors after donation, patient-reported outcomes should be analyzed separately from physiological outcomes.

Abbreviations
FEV1

forced expiratory volume in 1 s

FVC

forced vital capacity

HADS

Hospital Anxiety and Depression Scale

HRQOL

health-related quality of life

LDLLT

living-donor lobar lung transplantation

MCID

minimum to reach a clinically important difference

mMRC

modified Medical Research Council

PFT

pulmonary function test

PSQI

Pittsburgh Sleep Quality Index

SF-36

Medical Outcomes Study 36-item short form

Introduction

The success of living-donor lobar lung transplantation (LDLLT) is largely dependent on donor outcomes; however, comprehensive data concerning the outcomes of donors are lacking [1]. According to the Vancouver Transplantation Society's Forum Report on the care of live organ donors [2], all donors should be informed of both the potential morbidity and mortality associated with donor lobectomies and the potential impact of donation on their physiological and psychological well-being.

Researchers have previously applied health-related quality of life (HRQOL) parameters to the field of transplantation as a means to assess the outcome of the donors [3]. However, in contrast to assessments of preserved postoperative pulmonary function [4], HRQOL has not been prospectively studied in LDLLT donors [1].

We hypothesized that patient-reported outcomes would match physiological outcomes and would not worsen after LDLLT. We then prospectively evaluated multidimensional outcomes before and 1 year after donor lobectomies. The study population partly overlapped with the study population of a previous study that investigated the outcomes and pulmonary function in LDLLT [4].

Patients and Methods

Subjects

Thirty-five individuals who donated lobes for 16 bilateral LDLLTs and three single LDLLTs at Kyoto University Hospital from May 2009 to January 2012 were invited to participate in this study. The Ethical Committee of Kyoto University approved the study protocol (E-1429). We obtained written informed consent from all donors. Donor selection criteria are outlined in Table 1. All 35 donors met the donor criteria for LDLLT [5]. Before and at 1 year after lobectomy, we assessed donor pulmonary function and patient-reported measurements.

Table 1. Donor selection criteria for living-donor lobar lung transplantation
Relatives within the third degree or a spouse
Age, 20–60 years
ABO identical or compatible
No significant medical history or active medical problems
No recent viral infection
No abnormalities on the electrocardiograph and echocardiogram
No significant pulmonary pathology on computed tomography on donor side
Arterial oxygen tension ≥80 Torr
Forced vital capacity, forced expiratory volume in 1 s ≥85% of predicted
No previous thoracic operation on the side to be donated
Nonsmokers (if current smokers, cessation of smoking is required at the time of the offer for donation and continuous cessation is required after donor lobectomy)
Absence of coercion
Satisfactory psychosocial evaluation

Donor surgery

The full surgical management of the donors was performed as described previously [4, 5]. In summary, the surgeon performed a posterolateral thoracotomy under general anesthesia. Dissection in the fissure was performed in order to isolate the branches of the pulmonary artery going to the lower lobe and the inferior pulmonary vein. After placing vascular clamps in appropriate positions, the surgeon divided the pulmonary artery, pulmonary vein and bronchus and then closed the vascular and bronchial stumps. The thoracotomy was closed in a standard manner after placement of one or two chest tubes.

Pulmonary function tests

Investigators tested pulmonary function by using a Minato System 21 (Minato Medical Science Co Ltd., Osaka, Japan) to measure forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). We applied a prediction method by using calculated FVC according to the number of resected segments to postoperative spirometric parameters as we reported previously [2, 6, 7].

Patient-reported outcomes

HRQOL was assessed using the Japanese version of the Medical Outcomes Study 36-item short form (SF-36) [8-10]. The SF-36 contains 36 items that are aggregated into eight subscales, including physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE) and mental health (MH). The scores for each subscale range from 0 to 100; the higher the score, the higher the subscale HRQOL. The population norms for Japanese people are 89.1 (PF), 89.2 (RP), 73.8 (BP), 62.9 (GH), 62.8 (VT), 86.4 (SF), 87.8 (RE) and 71.6 (MH), respectively (age 50.5 ± 15.9 years, 1113 men and 1166 women) [10].

Dyspnea was evaluated using the Japanese version of the modified Medical Research Council (mMRC) dyspnea scale [9, 11]. This is a 5-point scale [1-4] based on degrees of various physical activities that precipitate dyspnea. Higher scores indicate worse dyspnea on the mMRC.

The psychological status was evaluated using the Japanese version of the Hospital Anxiety and Depression Scale (HADS) [8, 11, 12]. This scale consists of 14 items: seven for anxiety and seven for depression. Each item is scored from 0 to 3, where a score of 3 represents a state corresponding to the highest level of anxiety or depression. The sum of these items produces two subscales ranging from 0 to 21.

Sleep quality was measured using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) [6, 9]. Nineteen individual items generate seven component scores, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication and daytime dysfunction. Each dimension was scored from 0 to 3, and the seven component scores were then summed to yield a global PSQI score (ranging from 0 to 21), with a higher score indicating poorer sleep quality.

Patient-reported outcome assessments using questionnaires were self-administered a few days prior to surgery and 1 year after surgery.

Statistical analysis

Statistical analysis was performed using the StatView (version 4.5) software package (Abacus Concepts, Berkeley, CA). All values are presented as the mean ± the standard deviation of the mean. We used paired t-tests for pulmonary function values and Wilcoxon signed-rank tests for patient-reported measurements in order to compare values before and after donation. We used unpaired t-tests for pulmonary function values and Mann–Whitney U-tests for patient-reported measurements in order to compare the changes in measurements before and after donation between the following groups: donors who experienced complications requiring readmission and donors who did not, and donors whose recipients died and donors whose recipients did not. We analyzed the responsiveness of the SF-36 according to effect size, which represents the mean change in the score divided by the standard deviation of the baseline scores. Cohen described an effect size of 0.2–0.5 as being “small,” 0.5–0.8 as being “moderate” and an effect size greater than 0.8 as being “large” [13]. p-Values < 0.05 were considered statistically significant.

Results

Donor and recipient characteristics

Of the 35 donors who were invited to participate in this study, 33 met inclusion criteria. One donor did not answer the preoperative questionnaires. The recipient of the other donor, who answered the preoperative questionnaires, died soon after LDLLT because of primary graft dysfunction and did not answer the questionnaires at the conclusion of the 1-year period after donation.

The study included 19 female and 14 male healthy donors aged 40.5 ± 11.4 years. Participant height was 163.7 ± 9.0 cm, and weight was 60.6 ± 11.2 kg. %FVC (% of predicted value) was 117.9 ± 14.0%, and %FEV1 (% of predicted value) was 105.5 ± 11.3%. Seventeen donors donated the right lung, and 16 donated the left lung. None of the donors experienced life-threatening complications or died; however, five donors experienced postoperative complications requiring readmission. All of the donors were at home and without any specific limitations in daily life at 1 year after donation.

Regarding the recipients, the study included 10 female and 8 male recipients in the age range of 41.3 ± 35.4 years, including four pediatric recipients. The distribution of donor–recipient relationships was as follows: child, 13 donors; parent, 8 donors; sibling, 6 donors; spouse, 5 donors and aunt, 1 donor. Out of the 18 recipients, 2 (11%) died 1 year after LDLLT. Three donors experienced their recipients' deaths within 1 year after donation.

Patient-reported outcomes

Regarding HRQOL, four (PF, BP, GH and VT) of the eight SF-36 subscales showed a significant worsening of quality of life after donation (p < 0.05) (Tables 2 and S1). The changes in these four subscales assessed by the effect size were 0.36 (PF), 1.04 (BP), 0.39 (GH) and 0.31 (VT). This indicates that a large deterioration occurred in BP and a small deterioration occurred in PF, GH and VT. The proportions that exceeded half a standard deviation, an estimated minimum to reach a clinically important difference (MCID) [14], in the four subscales were 29% (PF), 70% (BP), 48% (GH) and 48% (VT).

Table 2. Preoperative and postoperative patient-reported measurements
 PreoperativePostoperativep-Value
  1. Higher scores indicate better status in the SF-36, and vice versa in the mMRC, HADS and PSQI.
  2. Numbers in parentheses indicate theoretical score ranges.
  3. SF-36, Medical Outcomes Study 36-item short form; PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health; mMRC, modified Medical Research Council; HADS, Hospital Anxiety and Depression Scale; PSQI, Pittsburgh Sleep Quality Index.
SF-36 (0–100)
PF97.2 ± 10.893.3 ± 6.800.0004
RP96.8 ± 14.293.9 ± 14.20.17
BP96.3 ± 13.382.5 ± 17.00.0005
GH81.2 ± 15.975.0 ± 18.20.042
VT71.6 ± 18.665.9 ± 19.30.036
SF89.4 ± 16.093.2 ± 13.30.32
RE90.9 ± 19.093.2 ± 15.80.43
MH75.8 ± 15.977.9 ± 14.40.86
mMRC dyspnea scale (0–4)0.0 ± 0.00.2 ± 0.40.043
HADS
Depression (0–21)3.2 ± 3.53.0 ± 2.80.80
Anxiety (0–21)3.7 ± 3.42.9 ± 3.40.023
PSQI (0–21)4.3 ± 3.04.7 ± 3.10.42

The preoperative mMRC dyspnea scale was 0 in all donors, and the postoperative score worsened by 0.2 ± 0.4 (p = 0.043). Although there were no significant changes in depression as assessed by HADS before and 1 year after donation (p = 0.80), postoperative anxiety as assessed by HADS was significantly lower than the preoperative value (p = 0.023). There was no significant change in PSQI before and after donation.

Comparison between donors who required readmission for postoperative complications and those who did not

In the SF-36 assessment, donors who required readmission for postoperative complications showed less worsening in the GH and more improvement in the SF than those who did not (p < 0.05) (Figure 1), and they did not show any significant differences in the changes in other six subscales. The mMRC dyspnea scale and HADS showed no significant differences between the groups at 1 year after donation (Table 3). Donors requiring readmission showed improvement in the PSQI score.

Figure 1.

Changes in eight subscale scores on the SF-36 after donation are shown in five donors who required readmission for postoperative complications (AC [+], white bars) and in 28 donors who did not (AC [−], black bars). Black and white bars indicate mean changes, and T-bars indicate standard deviations. p < 0.05, significant change between preoperative and postoperative values. *p < 0.05, significant difference between AC (−) and AC (+) groups. SF-36, Medical Outcomes Study 36-item short form; PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health.

Table 3. Changes in multidimensional measurements after donation among donors that required readmission versus donors that did not require readmission
 Donors who required readmission (n = 5)Donors who did not (n = 28)p-Value
  • Higher scores indicate worse status in the mMRC, HADS and PSQI.
  • PFT, pulmonary function test; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; mMRC, modified Medical Research Council; HADS, Hospital Anxiety and Depression Scale; PSQI, Pittsburgh Sleep Quality Index.
  • 1Postoperative value subtracted by preoperative value.
  • 2Statistically significant change between preoperative and postoperative values.
PFT (ratio to preoperatively estimated value, %)
FVC104.7 ± 11.7117.7 ± 11.720.02
FEV1106.6 ± 9.7115.6 ± 12.320.13
mMRC dyspnea scale10.0 ± 0.00.17 ± 0.3820.34
HADS1
Depression−0.6 ± 2.9−0.2 ± 2.70.73
Anxiety0.6 ± 2.7−1.1 ± 2.020.11
PSQI1−2.2 ± 1.620.9 ± 2.40.011

Comparison between donors whose recipients died and those whose recipients did not die

There was no significant difference in the postoperative pulmonary function between the groups (Table 4). However, in donors whose recipients died, all but one of the SF-36 subscales showed worsening mean scores (by more than 10 points) after donation, although significant differences were found in only two subscales of GH (p = 0.019) and SF (p = 0.032) between those whose recipients died and those whose did not (Figure 2). One potential for not achieving statistical significance may be small sample size (3 vs. 30). The mMRC dyspnea scale and HADS showed no significant differences between the groups at 1 year after donation. In contrast, donors whose recipients died developed significant worsening in PSQI scores after donation (p = 0.0037, Table 4).

Table 4. Changes in multidimensional measurements after donation in cases involving recipient death versus those not involving recipient death
 Donors experiencing recipient death (n = 3)Donors without recipient death (n = 30)p-Value
  • Higher scores indicate worse status in the mMRC, HADS and PSQI.
  • PFT, pulmonary function test; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; mMRC, modified Medical Research Council; HADS, Hospital Anxiety and Depression Scale; PSQI, Pittsburgh Sleep Quality Index.
  • 1Postoperative value subtracted by preoperative value.
  • 2Statistically significant change between preoperative and postoperative values.
PFT (ratio to preoperatively estimated value, %)
FVC107.8 ± 10.5116.5 ± 12.220.25
FEV1110.5 ± 12.0114.6 ± 12.420.59
mMRC dyspnea scale10.3 ± 0.60.1 ± 0.320.31
HADS1
Depression0.7 ± 0.6−0.3 ± 2.80.56
Anxiety0.0 ± 1.0−0.9 ± 2.320.50
PSQI14.3 ± 3.00.0 ± 2.20.0037
Figure 2.

Changes in eight subscale scores on the SF-36 after donation are shown in 30 donors without recipient death (RD [−], black bars) and in three donors with recipient death (RD [+], white bars). Black and white bars indicate mean changes, and T-bars indicate standard deviations. In the RD (+) group, all but one SF-36 subscale showed worsening mean scores by more than 10 points after donation, which contrasted with only one subscale (BP) in the RD (−) group. p < 0.05, significant change between preoperative and postoperative values. *p < 0.05, significant difference between RD (−) and RD (+) groups. SF-36, Medical Outcomes Study 36-item short form; PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health.

Discussion

Our study is the first to evaluate multidimensional outcomes prospectively in LDLLT donors before and after donation. While there is a low incidence of medical complications in donors in LDLLT, clinicians should pay more attention to their HRQOL during follow-up [2]. We found only two studies on postoperative HRQOL, but both studies presented a cross-sectional design assessing HRQOL of LDLLT donors only after donation [15, 16]. The present study offers two advantages over these previous studies. First, by prospectively examining both preoperative and postoperative measurements, we could directly analyze the impacts of donation. In the previous postoperative cross-sectional analysis [15, 16], it was not only impossible to compare their data with preoperative states, but patient demographics and a wide time range since donation (1–78 months [15] and 18–72 months [16]) may have affected the results. Second, we measured multiple outcomes, which enabled us to assess the impacts of donation from multiple dimensions.

As we previously reported [4], this study also showed that postoperative pulmonary function test results were significantly better than the preoperatively estimated values (p < 0.001). The actual values in this study demonstrated that the FVC and FEV1 at 1 year after donor lobectomy were 115.7 ± 12.1% and 114.2 ± 12.2% of the preoperatively estimated values, respectively. However, four of the eight subscales on the SF-36 significantly worsened at 1 year after donation. It should be noted that physical health or mental health impairments during a donors' daily activities might continue even up to a year after donor lobectomies. In particular, mean scores of BP worsened from 96.3 to 82.5. This is in contrast with the living-donor liver transplantation where most donors returned to baseline HRQOL within 6 months [17]. Because of this finding, surgeons should consider less invasive surgery (even in the case of donor lobectomies) such as video-assisted thoracoscopic lobectomy; however, clinicians need to weigh the excellent allograft function and recipient survival against donor impairment.

Individual subscale scores in the SF-36 in this study were relatively better than the Japanese standard values [10]. However, since most of the donors were healthy and young individuals, a relatively high postoperative HRQOL value may not mean that the value did not decrease after donation [17, 18]. The present, prospective study is of value since it highlights the importance of intra-patient changes in such scores.

Regarding dyspnea, the mMRC scale worsened significantly postoperatively in spite of preserved pulmonary function. Since there were significant correlations among the changes in the PF and BP subscales and the change in the mMRC dyspnea scale, this finding may be related to a worsening in the physical subscales on the SF-36 (data not shown). In a previous study of LDLLT [3], some donors complained of impaired exercise performance. Therefore, in addition to pulmonary function, researchers might need to assess dyspnea or functional capacities such as exercise performance in LDLLT donors.

We compared the changes from preoperative to postoperative states between five patients who required readmission for postoperative complications and 28 patients who did not. There was no significant difference in changes among six subscales of the SF-36. In patients requiring readmission, less worsening in the GH and more improvement in the SF were observed. In addition, patients requiring readmission showed no change in mMRC scores. Conversely, other patients showed a significant worsening. Thus, postoperative complications requiring readmission do not appear to affect HRQOL and dyspnea before and 1 year after donor lobectomies.

In the present prospective study, all subscales on the SF-36 worsened postoperatively in donors whose recipients died, and this worsening was associated with impaired sleep. Thus, the poor outcome of a recipient impaired the overall perceived health of the donor in spite of preserved pulmonary function. Clinicians might consider creating some protocols for tracking the donor's perception of health in cases of poor recipient outcome in LDLLT.

Prior to donation, LDLLT donors might be psychologically concerned about their own operative outcome as well as the outcome of their recipient. In the present study, donors showed a significant decrease in their anxiety scores according to the HADS at 1 year after donation. On the other hand, not only were there no significant differences in the perioperative changes between the donors whose recipients did or did not die, but the donors whose recipients did not die showed a significant decrease in their anxiety scores. These results indicate that LDLLT donors may tend to be psychologically distressed more by their own outcomes than is expected.

In this prospective study in LDLLT donors, we found a difference in the changes in outcomes of pulmonary function versus patient-reported outcomes. This might have been overlooked if the perioperative change in pulmonary function was the only parameter investigated. Previous studies in respiratory disease [11, 19] have found similar results: after medical interventions, the changes in physiological, objective measurements and the changes in psychosocial, subjective measurements were not parallel. To capture the overall perioperative impacts of donation on patients, the importance of multidimensional assessment should be emphasized.

MCID is an important concept in addition to statistically significant difference. However, MCID on the SF-36 has yet to be determined for donors after living transplantation. Similar studies in liver and kidney only compare preoperative and postoperative values. Considering that MCID is estimated to be around half a standard deviation [14], a worsening in BP would clearly exceed the MCID. Instead, we used the effect size. By using the effect size, we showed that (among the four subscales that showed a statistically significant change in Table 2) the worsening in BP was large and that the worsening in PF, GH and VT was small. However, analysis according to the MCID will also be necessary in the future.

Limitations of the present study included the small sample size and short duration of patient follow-up. For example, it might be difficult to support the additional attention given to the subgroup analyses because of the small number of donors that experienced postoperative complications or recipient death. This study, however, was a prospective study and there was a high response rate. Regarding a ceiling effect in the SF-36, the best possible scores were found in 82% (PF), 85% (RP), 91% (BP), 6% (GH), 3% (VT), 61% (SF), 70% (RE) and 6% (MH) preoperatively and in 33% (PF), 76% (RP), 30% (BP), 6% (GH), 6% (VT), 76% (SF), 76% (RE) and 3% (MH) postoperatively. However, because this study primarily focused on the stability or possible exacerbation of these scores at 1 year after donation, they probably would not have significantly affected the results. Furthermore, regarding the mMRC dyspnea scale, it is uncertain whether the small change seen in this study is clinically relevant. mMRC has recently been reported to lack sensitivity with regard to the changes in dyspnea and more sensitive, dyspnea-specific measurements might have been suitable [20, 21].

In conclusion, we prospectively evaluated multidimensional outcomes in LDLLT donors both before and after donation. We found possible postoperative deterioration in several aspects of HRQOL and dyspnea. We also found health impairments associated with impaired sleep quality in cases involving poor outcomes of the recipient. To capture the comprehensive outcomes in LDLLT donors after donation, patient-reported outcomes should also be longitudinally followed up separately from physiological outcomes. There is a question as to whether the practice of using living lung donors in Japan should continue. Understanding the real risks to the living lung donors, as shown in this study, might help propel Japan in the direction of making a successful, concerted, societal effort to increase standard deceased donation similar to most other countries.

Acknowledgment

This study was partly supported by a grant to the Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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