# Early mobilization and functional outcomes in cystic fibrosis patients after lung transplantation: A single-center retrospective study

Matthieu Reffienna, Jeremy Roussel, Gabor Kalman, Mathilde Labro, Charles Cerf, François Parquin

► To cite this version:

Matthieu Reffienna, Jeremy Roussel, Gabor Kalman, Mathilde Labro, Charles Cerf, et al.. Early mobilization and functional outcomes in cystic fibrosis patients after lung transplantation: A single-center retrospective study. Respiratory Medicine and Research, 2025, 88, pp.101184. 10.1016/j.resmer.2025.101184. hal-05135801

HAL Id: hal-05135801

https://hal.science/hal-05135801v1

Submitted on 30 Jun 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

ELSEVIER

Available online at

ScienceDirect

www.sciencedirect.com

Elsevier Masson France

EM|consulte

www.em-consulte.com

<figure><img src="image_3.png" /></figure>

Original article

# Early mobilization and functional outcomes in cystic fibrosis patients after lung transplantation: A single-center retrospective study

<figure><img src="image_4.png" /></figure>

Matthieu Reffienna<sup>a,*</sup>, Jeremy Roussel<sup>a</sup>, Gabor Kalman<sup>a</sup>, Mathilde Labro<sup>b</sup>, Charles Cerf<sup>a</sup>,
François Parquin<sup>c</sup>

ARTICLE INFO

Keywords:

Cystic fibrosis

Early mobilization

Lung transplantation

Physiotherapy

ABSTRACT

**Background:** Rehabilitation has been shown to enhance patient performance before and after lung transplantation, but limited data exist on its role during the immediate post-transplant phase in critical care units.

**Methods:** We conducted a single-center retrospective study. All adult patients who underwent bilateral transplantation for cystic fibrosis were included. Patients were followed from admission to discharge from critical care. All rehabilitation sessions were recorded. We aimed to evaluate the relationship between the amount of mobilization performed by the patient in critical care, and functional performance at discharge.

**Results:** We included 36 patients (21 males) with a median age of 29 years (IQR: 24.5–35.0) and a median critical care length of stay of 15 days (12.5–20). Patients performed a total of 388 sessions of rehabilitation. Out-of-bed mobilization started at a median of post-operative day 2.5 (IQR: 1.0–4.5), with the first walking session at day 3 (IQR: 2.0–4.5). A strong correlation was found between daily walking distance and functional performance, as measured by the 6-minute walk test, with a Pearson correlation coefficient of 0.70 (95 % CI: 0.48–0.84).

**Conclusions:** After lung transplantation for cystic fibrosis, early initiated rehabilitation in critical care is feasible and can improve patients' functional performance. These findings are promising, but require validation in other lung transplant populations.

## 1. Introduction

Rehabilitation is an essential part of the overall management of lung transplant (LTx) patients. Before transplantation, prehabilitation helps patients maintain or optimize their functional status [1,2] until surgery. After LTx, rehabilitation has been shown to enhance respiratory and functional capacity, improve quality of life, and increase survival rates [3–5]. However, the protocols in these studies begin only after discharge from critical care, which can be a significant period after LTx.

Data on post-transplant physiotherapy initiated in the ICU are limited. Tarrant et al. [6] showed that mobilization could be started early, but Song et al. [7] provided inconclusive results regarding functional performance at ICU discharge. During the acute post-LTx phase, loss of muscle mass and strength is rapid and significant [8], and may leave long-term functional sequelae [9]. However, early mobilization in the intensive care unit is feasible and safe [10], and can improve patients' functional outcome [11].

The objective of our study is to evaluate the relationship between the amount of mobilization performed by patients in critical care and their functional performance at the time of discharge.

## 2. Materials and methods

### 2.1. Study design

We conducted a retrospective, single-center observational study at Foch Hospital, France, a 600-bed university hospital. All adult patients undergoing bilateral transplantation for cystic fibrosis between January 1, 2019 and December 31, 2019 were included. Patients undergoing re-transplantation or combined transplantation were excluded. In addition, those listed under high-emergency status were excluded, as they were frequently already admitted to the ICU for several days prior to transplantation and often required extracorporeal life support such as ECMO. As a result, their perioperative management and rehabilitation protocols differed significantly from standard care, which could introduce bias and reduce comparability. Patients were followed from their admission through discharge within the hospital's 30-bed Critical Care Services (CCS), which comprise a 22-bed General Intensive Care Unit (GICU) and an 8-bed Thoracic Intensive Care Unit (TICU). This study was approved by the Foch hospital Research Ethics Committee on May 13, 2020 (registration number: IRB00012437).

<figure><img src="image_5.png" /></figure>

<footnote><sup>a</sup> Service de Réanimation Polyvalente, Hôpital Foch, Suresnes, France</footnote>

<footnote><sup>b</sup> Direction de la Recherche Clinique et de l'Innovation, Hôpital Foch, Suresnes, France</footnote>

<footnote><sup>c</sup> Unité de Soins Intensifs Respiratoires, Hôpital Foch, Suresnes, France</footnote>

<footnote>*Corresponding author.</footnote>

<footnote>E-mail address: m.reffienna@hopital-foch.com (M. Reffienna).</footnote>
<table><caption>**Table 1**
FITT reporting</caption><tr><td>Frequency</td><td>1 a 2 times a day; 1 time a day during weekends</td></tr><tr><td>Intensity</td><td>Borg scale from 3 to 7</td></tr><tr><td>Time</td><td>20 to 30 min</td></tr><tr><td>Type</td><td>Aerobics (walking, cycloergometer), muscle strengthening</td></tr></table>

## 2.2. Intervention

Early mobilization was delivered by a team of five physiotherapists available seven days a week, covering 30 CCS beds. Patients were transferred from GICU to TICU once extubated and hemodynamically stable. Rehabilitation was initiated as soon as the patient's neurological, hemodynamic, and respiratory status permitted. The program was multi-modal, incorporating in-bed mobilization, chair positioning, standing, use of a cycloergometer (Motomed® Letto and Viva 2, RECK-Technik GmbH & Co. KG), muscle strengthening, and walking (Déamborghini, BMB Médical). Patients received rehabilitation sessions twice daily, whenever their condition and the care schedule allowed, with walking sessions prioritized. On weekends, only one session per day was conducted due to the limited availability of physiotherapists. The application of the FITT principles (Frequency, Intensity, Time, and Type) is detailed in Table 1.

Upon discharge, patients underwent a functional assessment, including a 6-minute walk test (6MWT). The 6MWT was performed following standard protocols, despite the challenges inherent in critical care settings [12]. The predicted walking distance was calculated based on the patient's sex, age, and height [13].

## 2.3. Measurements

Age, sex, body mass index (BMI), Simplified Acute Physiology Score II (SAPS II) at admission, use of ex-vivo lung perfusion, extubation in the operating room, duration of postoperative mechanical ventilation, and lengths of stay in critical care (GICU and TICU) and in the hospital were recorded. We documented the dates of the patient's first time sitting in a chair and first walk relative to the date of the intervention. The number of rehabilitation sessions, total walking distance, and total pedaling time were adjusted to the number of days spent in critical care services (CCS) to quantify the rehabilitation performed.

## 2.4. Outcomes

The primary objective of the study was to evaluate the relationship between the amount of mobilization performed by patients and their functional capacity at discharge. The primary endpoint was the correlation between daily walking distance (measured in meters per day) and 6MWT score as a percentage of the theoretical value (%6MWT). Secondary objectives included assessing the feasibility of early and intensive rehabilitation following transplantation. The secondary outcome measures were the timing of initiation of chair sitting and walking (in days post-transplant), as well as the number of rehabilitation sessions per day.

## 2.5. Statistical analysis

Prospectively recorded daily data in Centricity™ Critical Care (GE) software were retrospectively analyzed. Statistical analyses were conducted using SAS software version 8.3, with a significance threshold set at 0.05. Results were presented graphically to facilitate interpretation and to illustrate the relationships identified.

Quantitative variables were summarized as medians and interquartile ranges (IQR), while qualitative variables were described using frequencies and percentages. The initial analysis involved assessing the correlation between the average daily distance covered during rehabilitation sessions and the theoretical percentage of the 6-minute walk distance (%6MWT). Scatterplots were used to explore the relationship between quantitative variables. By observing these plots, we were able to infer the shape of the relationship and then test its strength. The Pearson correlation coefficient, along with its 95 % confidence interval and significance test, was calculated to assess the strength and direction of the linear relationship.

To further explore the association between variables and evaluate the causal effect of rehabilitation on the 6MWT, a linear regression analysis of %6MWT based on mean daily walking distance was performed. The assumptions of the regression model—normality and homoscedasticity of residuals—were verified.

Given the potential for non-linearity in the relationship, a local LOESS (Locally Estimated Scatterplot Smoothing) regression model with first-degree polynomials was used to determine localized relationships between rehabilitation and %6MWT and to plot a smoothed curve. Based on the breakpoint identified by the LOESS regression, segmented linear regressions were performed for both segments of the data. This

<figure><img src="image_6.png" /><figcaption>**Fig. 1.** Flowchart.</figcaption></figure>
<table><caption>**Table 2**
Baseline characteristics of patients</caption><thead><tr><th>Baseline</th><th>Median / Number<br>(n = 36)</th><th>(Q1-Q3) / Percentage</th></tr></thead><tbody><tr><td>Age (years)</td><td>29.0</td><td>(24.5-35.0)</td></tr><tr><td>Men (n)</td><td>21</td><td>58.3</td></tr><tr><td>Body Mass Index (kg/m<sup>2</sup>)</td><td>19.2</td><td>(17.2-20.9)</td></tr><tr><td>Ex vivo lung perfusion (n)</td><td>16</td><td>44.4</td></tr><tr><td>Extubation in the operating room (n)</td><td>20</td><td>55.5</td></tr><tr><td>Duration of mechanical ventilation (d)</td><td>0</td><td>(0-3.0)</td></tr><tr><td>Simplified Acute Physiology Score II<br>(pts)</td><td>31.5</td><td>(24.5-37.0)</td></tr><tr><td>Lengths of stay in critical care services<br>(d)</td><td>15.0</td><td>(12.5-20.0)</td></tr><tr><td>Lengths of stay in hospital (d)</td><td>27.5</td><td>(23.0-35.5)</td></tr><tr><td>6-minutes-walk test pre-LTx<br>(%theoretical)</td><td>64.4</td><td>(56.8-77.5)</td></tr><tr><td>First sit in chair (D+)</td><td>2.5</td><td>(1.0-4.5)</td></tr><tr><td>First walk (D+)</td><td>3.0</td><td>(2.0-4.5)</td></tr><tr><td>Mean walking distance (m/j)</td><td>206.0</td><td>(145-328)</td></tr><tr><td>Mean cycling duration (min/j)</td><td>6.5</td><td>(5.4-7.7)</td></tr><tr><td>Number of sessions (/j)</td><td>0.9</td><td>(0.8-1.1)</td></tr><tr><td>6-minutes-walk test post-LTx<br>(%theoretical)</td><td>56.5</td><td>(46.1-70.5)</td></tr><tr><td>Death</td><td>0</td><td>0</td></tr></tbody></table>

allowed us to compare the impact of average daily walking distance on %6MWT below and above the identified threshold.

To assess the robustness of the main findings, several instrumental and adjustment variables were tested, including length of stay in critical care, number of rehabilitation sessions, and session duration.

# 3. Results

## 3.1. Population characteristics

In 2019, 82 lung transplants were performed at Foch Hospital. Forty adult cystic fibrosis patients received a first bilateral lung transplant outside of high-emergency conditions. Four patients were excluded due to missing data (missing discharge 6MWT or rehabilitation data) (Fig. 1).

The 36 patients included in the analysis had a median age of 29 years (IQR: 24.5-35.0), and 58.3 % were male (Table 2). The median duration of mechanical ventilation in GICU was 0 days [IQR: 0-3], with 20 patients extubated in the operating room.

The median length of stay in critical care (GICU followed by TICU) was 15 days (IQR: 12.5-20). Patients began mobilization by sitting in a chair on postoperative day 2.5 (IQR: 1.0-4.5) and started walking on day 3 (IQR: 2.0-4.5). The median frequency of rehabilitation was 0.9 sessions per day (IQR: 0.8-1.1). Patients walked a median distance of 206 m per day (IQR: 145-328) and cycled for a median of 6.5 min per day (IQR: 5.4-7.7).

None of the patients died during their critical care stay.

## 3.2. Correlation

We analyzed the relationship between average daily walking distance and the 6MWT performance, expressed as a percentage of the theoretical value. Data normality was confirmed, and the scatterplot demonstrated a clear positive trend between walking distance during rehabilitation and 6MWT performance (Fig. 2).

The Pearson correlation coefficient was 0.70 (95 % CI: 0.48-0.84), indicating a strong positive linear correlation between % theoretical 6MWT and mean daily walking distance during the CCS stay. As rehabilitation walking distance increased, % theoretical 6MWT—and thus functional capacity—increased significantly.

## 3.3. Linear regression

To further examine the linear relationship between % theoretical 6MWT and average daily walking distance, a simple linear regression was performed (Fig. 3). The resulting equation was: %6MWT = 34.0 + 0.10 × Daily walking distance. The coefficient of determination (R²) was 0.49, meaning that 49 % of the variation in %6MWT was explained by the average daily walking distance during rehabilitation. This suggests a moderately strong linear relationship.

A significant linear association was found between daily distance walked and %6MWT (p < 0.001), with each additional 10 m walked per day associated with a 1-point increase in %6MWT. Testing other

<figure><img src="image_7.png" /><figcaption>**Fig. 2.** Scatterplot with 95 % forecast ellipse.</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>Fig. 3. Linear regression.</figcaption></figure>

variables, such as CCS length of stay, number of rehabilitation sessions, and session duration, did not improve the model.

### 3.4. LOESS regression

To further explore this relationship, we conducted a LOESS regression (Locally Estimated Scatterplot Smoothing) (Fig. 4, Table 3), which

identified a breakpoint at 320 m of average daily walking distance, suggesting different linear relationships on either side of this threshold.

The slope ratio was 1.90 (0.137/0.072), indicating that the impact of walking distance on %6MWT was nearly twice as strong when daily distance exceeded 320 m. Beyond this threshold, the influence of walking distance on %6MWT increased markedly, making 320 m a critical point for improved functional capacity.

<figure><img src="image_9.png" /><figcaption>Fig. 4. Adjustment curve.</figcaption></figure>
<table><caption>**Table 3**
LOESS regression results</caption><thead><tr><th rowspan="2">Daily distance walked</th><th colspan="3">Local linear regressions</th></tr><tr><th>Intercept</th><th>Coefficient (β)</th><th>%MWT theoretical predicted</th></tr></thead><tbody><tr><td>≤ 320 m/day</td><td>39.4</td><td>0.072</td><td>44 % à 63 %</td></tr><tr><td>> 320 m/day</td><td>18.0</td><td>0.137</td><td>64 % à 98 %</td></tr></tbody></table>

# 4. Discussion

## 4.1. Key results

We demonstrated a strong correlation between daily walking distance during critical care and functional performance on the 6-minute

walk test in cystic fibrosis patients following lung transplantation. Moreover, physiotherapist-led mobilization could be initiated early in the ICU, with patients first getting out of bed at a median of $D + 2.5$ and beginning to walk by $D + 3$.

Two previous studies have evaluated the feasibility of early mobilization in the ICU. In Song et al.'s 2018 study, rehabilitation was initiated at $D + 7.5$, and only 64 % of patients were able to walk at discharge [7]. Our findings suggest that rehabilitation can be started significantly earlier, with the first out-of-bed exercises performed as early as $D + 2.5$, and some patients even walking on $D + 1$. This early mobilization, despite the extensive postoperative equipment, was facilitated by dedicated tools such as the Déamborghini (BMB Medical) (Fig. 5), which helped manage multiple devices more easily.

Tarrant et al. [6] also investigated the timing of mobilization and the amount of rehabilitation. While their findings confirmed the feasibility of initiating rehabilitation by $D + 2$, their study only measured the

<figure><img src="image_10.png" /><figcaption>**Fig. 5.** Walking a patient at $D + 2$ using a Déamborghini.</figcaption></figure>
duration of physiotherapy sessions during the first and last three days of ICU stay. In contrast, our study not only quantified the amount of rehabilitation in terms of walking distance and pedaling time, but also demonstrated a clear correlation between daily walking distance and functional performance at discharge, as measured by the %6MWT.

## 4.2. Limitations

The first limitation of this study is that it was conducted at a single center. In 2019, Foch Hospital was the leading lung transplantation center in France, particularly for cystic fibrosis patients. The high transplant volume of our center reflects considerable experience and expertise in patient management, which may result in center-specific outcomes. Over recent years, Foch Hospital and its transplant team have made significant investments in patient rehabilitation within critical care services, ensuring a high physiotherapist-to-patient ratio and the availability of dedicated resources. This emphasis on rehabilitation may limit the generalizability of our results to other centers with less experience and fewer resources.

The second limitation concerns the study population. To ensure homogeneity, we included only patients who underwent bilateral lung transplantation for cystic fibrosis in 2019. However, since the marketing authorization of Kaftrio® (ivacaftor/tezacaftor/elexacaftor) for cystic fibrosis patients in France in 2021, the number of lung transplants for this condition has decreased by 88% (from 95 to 8 patients between 2019 and 2023) [14]. This reduction has also been accompanied by an aging transplant population, with the average age increasing from 48.8 years in 2019 to 54.3 years in 2023. Consequently, our program will likely need to be adapted to other pathologies, such as chronic obstructive pulmonary disease or pulmonary fibrosis, as these patients typically present with more comorbidities, potentially complicating physiotherapy sessions.

Finally, the retrospective, single-group study design does not allow us to conclude that mobilization was the sole independent factor contributing to improved clinical outcomes. Other variables may have influenced patients' overall condition, including care intensity, postoperative complications, emotional support, nutritional status, and individual motivation. These factors were not assessed in this retrospective analysis, which may have affected our findings.

## 4.3. Interpretation

Regarding the primary outcome of our study, it is likely that patients who achieved greater walking distances also had a better overall clinical status. The association between mobilization level and functional performance reflects a strong correlation; however, other factors may have contributed to this outcome. Although patients were encouraged to walk as far as their condition allowed during each session, no specific walking distance target was defined. Interestingly, the breakpoint observed at 320 m coincided with two complete laps around the critical care unit, suggesting a possible environmental influence on patient walking behavior.

While the main aim of the study was to assess the relationship between daily walking distance and functional performance, the rehabilitation sessions also included cycling, muscle-strengthening exercises, and quadriceps strength assessments with a dynamometer. Although these additional data were not analyzed here, it is worth noting that the rehabilitation program was proactive, multimodal, and conducted multiple times per day.

Regarding rehabilitation intensity, patients participated in fewer than one session per day on average, despite a protocol recommending two daily sessions. This discrepancy is likely due to competing medical priorities (e.g., bronchoscopy, plasma exchange) and nursing interventions (e.g., dressings, equipment adjustments), particularly in the initial GICU days. Given the positive outcomes observed, collaborating with the multidisciplinary team to reorganize care delivery may help

integrate rehabilitation more fully into the early postoperative routine through a standardized protocol.

## 4.4. Implications on physiotherapy practice

Our results support the early initiation of mobilization for lung transplant patients with cystic fibrosis. Despite extensive postoperative equipment, early out-of-bed mobilization and ambulation are feasible. Patients should be encouraged to walk as much as their condition allows to improve functional capacity by ICU discharge. Implementing these findings requires adequate human and material resources.

# 5. Conclusion

In cystic fibrosis patients who have undergone bilateral lung transplantation, early rehabilitation can be initiated in the ICU. Furthermore, there is a strong correlation between daily walking distance and functional performance, as measured by the 6-minute walk test, at ICU discharge.

Further research is needed to assess whether these improvements are sustained over time and contribute to long-term quality of life. It also remains to be determined whether these findings are generalizable to other patient populations and pathologies that are more susceptible to sarcopenia

## Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

We would like to thank the physiotherapists who participated in this project. Our thanks also go to Flavie Barret and Pauline Touche from the Research Department of Foch Hospital for their methodological support.

## References

[1] Langer D. Rehabilitation in Patients before and after Lung Transplantation. Respiration 2015;89(5):353-62. doi: 10.1159/000430451.

[2] Hoffman M, Chaves G, Ribeiro-Samora GA, Britto RR, Parreira VF. Effects of pulmonary rehabilitation in lung transplant candidates: a systematic review. BMJ Open 2017;7(2):e013445. doi: 10.1136/bmjopen-2016-013445.

[3] Ulvestad M, Durheim MT, Kongerud JS, Lund MB, Edvardsen E. Effect of high-intensity training on peak oxygen uptake and muscular strength after lung transplantation: a randomized controlled trial. J Heart Lung Transplant 2020;39(9):859-67. doi: 10.1016/j.healun.2020.06.006.

[4] Candemir I, Ergun P, Kaymaz D, Demir N, Taşdemir F, Sengul F, et al. The efficacy of outpatient pulmonary rehabilitation after bilateral lung transplantation. J Cardio-pulm Rehabil Prev 2019;39(4):E7-12. doi: 10.1097/HCR.0000000000000391.

[5] Langer D, Burtin C, Schepers I, Ivanova A, Verleden G, Decramer M, et al. Exercise training after lung transplantation improves participation in daily activity: a randomized controlled trial. Am J Transplant 2012;12(6):1584-92. doi: 10.1111/j.1600-6143.2012.04000.x.

[6] Tarrant BJ, Holland A, Le Maitre C, Robinson R, Corbett M, Bondarenko J, et al. The timing and extent of acute physiotherapy involvement following lung transplantation: an observational study. Physiother Res Intl 2018;23(3):e1710. doi: 10.1002/pri.1710.

[7] Song JH, Park JE, Lee SC, Kim S, Lee DH, Kim EK, et al. Feasibility of immediate intensive care unit pulmonary rehabilitation after lung transplantation: a single center experience. Acute Crit Care 2018;33(3):146-53. doi: 10.4266/acc.2018.00129.

[8] Fazzini B, Märkl T, Costas C, Blobner M, Schaller SJ, Prowle J, et al. The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis. Crit Care 2023;27(1):2. doi: 10.1186/s13054-022-04253-0.
[9] Herridge MS, Diaz-Granados N, Cooper A, Mehta S, Slutsky AS. Functional disability 5 years after acute respiratory distress syndrome. n engl j med 2011. doi: 10.1056/NEJMoa1011802.

[10] Paton M, Chan S, Serpa Neto A, Tipping CJ, Stratton A, Lane R, et al. Association of active mobilisation variables with adverse events and mortality in patients requiring mechanical ventilation in the intensive care unit: a systematic review and meta-analysis. Lancet Respirat Med 2024;12(5):386-98. doi: 10.1016/S2213-2600(24)00011-0.

[11] Burtin C., Clerckx B., Robbeets C., Ferdinande P., Langer D., Troosters T., et al. Early exercise in critically ill patients enhances short-term functional recovery*: critical

Care Medicine. 2009;37(9):2499-505. https://doi.org/10.1097/CCM.0b013e3181a38937

[12] Statement ATS. Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med 2002;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102.

[13] Chetta A, Zanini A, Pisi G, Aiello M, Tzani P, Neri M, et al. Reference values for the 6-min walk test in healthy subjects 20-50 years old. Respir Med 2006;100(9):1573-8. doi: 10.1016/j.rmed.2006.01.001.

[14] Agence de la Biomédecine. Rapport médical et scientifique 2023. https://rams.agence-biomedecine.fr/greffe-cardio-pulmonaire-et-pulmonaire-0. [Accessed October 10, 2024]