Adapted Physical Activity, Exergaming and Relaxation by biofeedback in Hematological intensive care unit – Study protocol of a Randomised Controlled Trial (APAER-H trial)

doi:10.21203/rs.3.rs-4964387/v1

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Study protocol

Adapted Physical Activity, Exergaming and Relaxation by biofeedback in Hematological intensive care unit – Study protocol of a Randomised Controlled Trial (APAER-H trial)

https://doi.org/10.21203/rs.3.rs-4964387/v1

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Background:

Hematological malignancies and their treatments are known for their significant adverse effects on health-related quality of life (QoL). During high-dose treatments in Hematological Intensive Care Units (HICU), Adapted Physical Activity (APA) is recognised for its role in maintaining physical fitness and limiting fatigue. Psychological and emotional states are also impaired, with anxiety levels significantly increasing in this specific context. Limited information is available about this topic. However, APA has been shown to reduce anxiety in various population, including oncological patients. Furthermore, adding new technology as exergaming or Heart Rate Variability Biofeedback (HRVB) relaxation tools could be an effective way to regulate emotions during treatments while providing the health-benefits of APA. APA, Exergaming and Relaxation by biofeedback in Hematological intensive care units protocol is a randomised, controlled trial. Our study is designed to evaluate the effects of APA programs during high-dose treatments in HICU on anxiety, fatigue level, functional capacities, immune system activity, and global QoL. Additionally, we aim to analyse the added-value of using specific devices as Exergaming and HRVB relaxation on the aforementioned parameters. We expect a difference in effectiveness between the programs concerning emotional regulation.

Methods:

Ninety patients (18–75 years), with various forms of hematological malignancies admitted to HICU, with haematologist’ approval for APA, will be randomly allocated in a 1:1:1 ratio to three 3-week APA groups: APA only (APA), APA by Exergaming (EXER), APA + HRVB relaxation (BIO). APA sessions will consist of moderate aerobic training on cyclo-ergometer (classical stationary bicycle for APA, BIO and connected ergometer in EXER), 3 times per week. The HRVB training will consist of controlled breathing exercises with biofeedback of heart rate variability at the end of each APA session (BIO).

Discussion:

The primary outcome is to evaluate the effect of 3 short APA programs on state anxiety (HADS; STAI-YA) and fatigue (MFI-20). The secondary outcomes will assess the effects on physical fitness (2MWT; FTSST), QoL (EORTC-QLQC30) and immune system functioning (blood samples). All of these assessments are evaluated initially (T1) and directly after (T2).

Trial Registration:

APAER-H protocol (version 1.1 of the 14/06/2022) was approved by the French Sud Mediteranian III ethical committee and registered on ClinicalTrials.gov: NCT05475600 (https://clinicaltrials.gov/).

Adapted Physical Activity

Hematological Malignancies

Anxiety

Fatigue

Exergaming

Relaxation

Heart Rate Variability Biofeedback

Hematological Malignancies (HM) are a diverse group of cancerous conditions originating from hematopoietic cells of the bone marrow and lymphoid system, representing approximately 12% of all cancer cases¹. Defined by Diebold et al. (2008)² as neoplasms arising from these specific cellular lineages, HM are commonly referred to as "blood cancers." Characterized by the proliferation of malignant cells within the hematopoietic system, HM disrupt normal hematopoiesis and physiological processes³. Treatment of HM often necessitates intensive interventions, including high-dose therapies with or without Hematological Stem Cell Transplant (HSCT), typically administered within specialized facilities such as Hematological Intensive Care Units (HICU), where patients undergo prolonged periods of isolation in sterile environments lasting a minimum of 21 days. Despite the potential therapeutic benefits of these treatments, patients often experience significant adverse effects on both physical and psychological well-being. Notably, profound fatigue⁴ and decline in muscular and aerobic capacities have been observed^5–8, leading a decreased autonomy in Activities of Daily Living (ADL) and a reduced overall Quality of Life (QoL)^8–13. Furthermore, the restrictive nature of HICU care protocols exacerbates the risk of functional decline, with sedentary behaviors and social isolation contributing to increased levels of anxiety and depression^5,6,14,15. In addition, anxiety has been shown to have a detrimental influence on the Immune System (SI) or inflammatory factors¹⁶, which are also factors influencing the progression of the disease.

Contemporary healthcare strategies advocate for integrated supportive care approaches, with Adapted Physical Activity (APA) emerging as a key component. Recommendations from national and international healthcare bodies such as the French National Authority for Health (HAS), the World Health Organization (WHO), and the French National Cancer Institute (INCa) endorse the incorporation of APA interventions during and following HICU treatments^17,18. Accumulating evidence underscores the beneficial effects of regular APA participation in preserving or enhancing physical functions and promoting psychological well-being throughout the cancer care continuum.

Adapted Physical Activity & Hematological malignancies:

During HICU treatments, APA practice is well known for its beneficial effects on physical functioning and fatigue^19–26. Previous studies showed that regular APA practice leads to improve, maintain or recover muscular strength and endurance abilities. It has also been demonstrated that APA limits the increase of fatigue severity. These benefits exist whenever the APA practice starts (before, during or after HICU Stay).

APA is increasingly recommended for cancer patients^27,28, and it is well known to be safe and not to interfere with HICU treatments^{4,7,9,11,25,29}. Different programs have been tested with various durations. It seems that all types of activities (aerobic, strength training, mixt) have positive effects on physical fitness, fatigue levels and QoL of HICU patients^{21,23–25,30–32}. To our knowledge, all these health benefits have been demonstrated only in long term programs (12 weeks on average). Most of APA programs tested began after the HICU phase or extended after hospital discharge. Surprisingly, short programs that take place only during hospital stay (+/- 3 weeks) has not been study yet. So, the originality of our work is to demonstrated the positive effects of a short duration program on the previously mentioned parameters.

APA and Anxiety:

Anxiety has a high prevalence in oncological population and more specifically in HICU populations³³. Hematological patients have higher risks of developing anxiety¹² and it has been confirmed that HICU patients can exhibit a high level of anxiety^11,31. According to Prieto et al., (2004)³⁴, higher levels of anxiety appear at the admission time in HICU. However, this parameter remains not much studied in this specific population. To our knowledge, no study strictly states on the effects of APA practice on anxiety during HICU. In this light, it would be an interesting way to investigate the potential methods to modulate and reduce anxiety.

Anxiety refers to a complex mechanism with different characteristics. According to Spielberger (1983)³⁵, anxiety is defined as "a transient emotional state or condition of the human organism characterised by subjective feelings of tension and apprehension and by heightened autonomic nervous system activity." This definition illustrates the complexity of anxiety and highlights the existence of its emotional manifestations and physiological repercussions. Spielberger distinguishes 2 components of anxiety: Trait anxiety and State anxiety. Trait anxiety refers to a component of personality or character. State anxiety is characterised by physiological and neurological reactions to an anxiogenic situation. Anxiety could constitute a disabling difficulty³⁶, serving as both a cause and a consequence of psychophysiological impairment. It can be a symptom of psychological distress and a component of pathological decompensation¹⁸. Psychological distress (i.e. the association of anxiety and depression) before treatments and the anxiety developed during the treatment have physiological consequences like lower white blood cells recovery¹⁶ and release of tumor growth factors that favour the development of cancer^16,37.

APA appears to be an effective way to reduce anxiety in different populations³⁸. However, it remains difficult to draw definitive conclusions about this topic, essentially because of the diversity and heterogeneity of the population treated for cancer. Moreover, anxiety rarely constitutes the primary criteria of the we could have access to. The use of drugs could hinder or minimise the effects of APA on anxiety¹⁸. Even if the research is still scarce about the effects of APA on anxiety level in a HICU context, evidences exist in other cases of cancer. Aerobic exercise helps to reduce anxiety level in different populations including oncological patients during and after treatments^39–42. Specks et al. (2010)⁴⁰ demonstrate in a meta-analysis that regular APA practice (30 to 45 minutes per session, 3 to 5 sessions per week) leads to lower anxiety level during treatment in various oncological populations including leukemia and lymphoma patients. Buffart et al. (2012)⁴³ highlighted that yoga practice associated with relaxation, respiration or meditation technique can decrease anxiety level during and after treatments. Thus, analysing the effects of a program including aerobic APA associated with relaxation techniques would be an interesting way to explore.

APA and Fatigue:

Ninety percent of hematological patients reported severe psychological and physical fatigue⁹. This fatigue is the result of reduced activity levels, which turn negatively impacts health by causing functional decline. In the same vain, Vermaete et al. (2013)⁸ concluded that a high level of fatigue is correlated with a low level of activity.

During intensive treatment in HICU, fatigue is the most frequently reported symptom and it has been described as the most limiting one²¹. In 2011, Baumann et al.²⁵ demonstrated that physical activity programs during treatment help to reduce the impact of fatigue. Previous studies have shown that APA practice during treatment significantly decreases the severity of fatigue in individuals, both during and after treatment. Mixed programs combining aerobic and resistance training appear to be the most effective in reducing fatigue. Baumann et al. (2011)²⁵ demonstrated a fatigue increase of about 46.6% among patients admitted in HICU. However, this fatigue increase is limited when patients practice APA alongside usual care. And according to the latter authors, fatigue level only increases slightly (4.8%). Wiskemann et al. (2011)³⁰ highlighted a 28% increase in fatigue among individuals receiving standard care upon discharge from hospitalisation. Conversely, when they also practice APA during hospital stay, fatigue is reduced by 15%. Although each intervention shows a limitation or decrease in fatigue, results may vary depending on the specificities of the program implemented.

Other studies have demonstrated the positive impact of APA practice on fatigue among individuals undergoing treatment in HICU. Depending on the program implemented, a reduction and/or limitation of fatigue is observed in each group receiving APA interventions^19,21,31,32.

APA, Immune System & Inflammation factors:

For HICU patients, high-dose treatments reduce the bone marrow activity and patients get into aplasia period. During this period, they have no more leukocyte and no more platelet to struggle risks of infection and bleeding. The immune system's capacity to fulfill its protective function is compromised in individuals undergoing treatment for HM⁴⁴. However, engaging in moderate APA has been demonstrated to increase immune system efficiency and bone marrow activity^47–49. Different studies have demonstrated beneficial influence of APA practice on these inflammatory factors. C-Reactive Protein (CRP) is the most commonly used marker of inflammation in HICU patients and is known to increases during HICU treatments. Lavie et al., (2011)⁴⁵, highlighted an inverse relation between concentration of CRP and APA practice. Moreover, Sitlinger et al. (2020)⁴⁴ put forward the positive effects of physical exercise on neutrophil, macrophages (enhance anti-inflammatory macrophages and reduce functions of inflammatory macrophages), T cells and Natural Killers Cells function tend to mitigate inflammation and improve tumor cells recognition and killing. In this light, leukocytes and neutrophils counts, lymphocytes rates and CRP levels in biological reports are collected and analysed current APAER-H to note if APA practice induces modifications in inflammation in HICU patients.

Exergaming:

However, several side effects in HICU can hinder regular APA practice. To facilitate and maintain a sufficient daily activity, the use some new devices could be an efficient strategy. Exergaming can be one of them to add fun and to favour practice during complex treatment phases. “Exergaming” comes from the association of “Exercise” and “gaming”. At the beginning, exergaming devices have been created for general public (Nintendo Wii, Xbox Kinects, serious game, …) and consist in exercise and training through fun or recreative situations. Using an exergaming device helps make the practice more engaging and overcome certain barriers (motivation, fatigue). The goal here is to allow people to do more physical exercise by using videogames. Its effectiveness has been proven in rehabilitation programs with different pathologic populations (neurological, oncological, motor disabilities, …)^46,47. Associating these virtual devices with effective physical exercises leads to physical and psychological benefits. Rehabilitation programs including exergaming allow an improvement of muscular strength, balance and cardio-respiratory fitness in oncological patients⁴⁸. Then, this type of protocols could lead to improvement of depression score, anxiety level and well-being⁴⁸. To our knowledge, no study has investigated the added value of a cycloergometer exergame device in HICU yet. Moreover, exergaming increases adherence to practice⁴⁹ and duration of practice⁵⁰. Thus, it may be a good way to favour APA practice and reduce anxiety during an HICU stay.

Relaxation: Heart Rate Variability Biofeedback Training

Biofeedback training is a component of relaxation training. A biofeedback device is a tool that provides real-time feedback on the functioning of the nervous system. The objective is to guide users to become aware of their bodily information and ultimately associate it with sensations and enabling them to more effectively control these bodily processes. Biofeedback is an effective method for raising awareness of the effects of emotions on the body and on the Autonomic Nervous System (ANS)⁵¹. One biofeedback technique is the Heart Rate Variability Biofeedback Training (HRVBT), which focuses on variations in heart rate over time. Heart Rate Variability (HRV) provides information about the ANS functioning. At rest, HRV reflects the adaptation of the cardiac system to changes⁵² and serves as a reliable biomarker of cardiac health. HRVBT has shown its effectiveness in managing chronic diseases, including cancer⁵². In their review, the authors highlighted the feasibility and the effectiveness of HRVBT on various parameters, including anxiety and inflammatory state. El-Jawhari et al. (2016)¹¹ reported high anxiety levels in HICU patients. Using HRVBT could assist in modulating anxiety levels. The objective of HRVBT is to breathe at approximately 6 breath cycles per minute, which synchronises the resonance of the HR to the respiratory cycles. This synchronisation positively impacts the cardiorespiratory system, improving the balance of the ANS and the regulation of the inflammatory responses^56–58. HRVBT leads to a reduction in the inflammatory process by increasing the vagal nerve activity. Increased vagal efferences produce an anti-inflammatory effect by inhibiting the release of cytokines. It could appear then that reducing anxiety and inhibiting cytokine release through the vagal nerve modulation could help to limit the inflammation and may promote cellular recovery. Maintaining functional capacities and reducing negative emotional states could contribute in a fatigue decrease. Moreover, biofeedback program improves QoL and immune response in other cancer population^59,60. Lastly, APA associated with HRVBT relaxation could be an effective support care strategy to reduce anxiety level in HICU patients.

APAER-H study provides 3 aerobic programs based on cycloergometer practice and dispensed 3 times per week in HICU: APA classic (APA), APA associated with HRVBT (BIO) and APA by Exergaming (EXER).

OBJECTIVES AND HYPOTHESIS:

The objectives of this APAER-H study are to reduce state anxiety and psychological fatigue impact on QoL and to maintain or improve functional capacities and reduce physical fatigue.

We hypothesised that 1/ each of the 3 programs (APA classic, BIO, EXER) leads to the objectives specified above. 2/ APA associated with biofeedback relaxation reduces more state anxiety level than APA with exergaming that is more effective than APA classic. 3/ APA with Exergaming and biofeedback practice gender more satisfaction and adhesion than APA classic.

The APAER-H protocol is a monocentric, 3 parallel arms, randomized controlled trial in adult hematological patients who are currently undergoing high dose treatment for Hematological Malignancy (HM) in Hematological Intensive Care Unit (HICU) of the CHR Metz-Thionville, Mercy hospital, France. The inclusion schedule provides a total inclusion period of 24 months and patient inclusion began in December 2022. This manuscript was written according to Standard Protocol Items: Recommendations for Interventional Trials guidelines⁶¹. The study was approved by the national French ethics committee (Sud Méditerranée III Ethical Committee) and is registered on ClinicalTrials.gov.

Study population

Inclusion criteria: Our study includes French-Speaking patients: aged 18–75 years old, with various acute forms of hematological malignancies, undergoing intensive treatments phases in HICU and have the hematologist’s approval for APA, who have given written informed consent prior to participation to the study.

Non-inclusion criteria: patients are excluded if they have medical contraindication to physical exercise, do not speak or understand french language (written and/or oral), do not have medical insurance, or they are already being involved in another exclusive research protocol.

Interventions:

Our intervention currently consists in 3 supervised APA programs for patients undergoing intensive treatments in HICU. A randomisation process determines the affiliation group for each patient. Whatever the affiliation, each patient practices aerobic exercise on cycloergometer 3 times per week during 30 to 60 minutes at a controlled intensity ranging from mild to moderate (3 to 7 on the Modified Borg Scale which corresponds to 50 to 75% HRmax) under an APA instructor’s supervision. The first group practices APA program on a classical cycloergometer (APA). The 2nd group (EXER), practices on a connected cycloergometer device. The 3rd group (BIO), practices on a classical cycloergometer and realises relaxation with Heart Rate Variability Biofeedback Training (HRVBT) at the end of each session (Fig. 1).

Sessions are individual and supervised by the APA instructor. The program takes place during all the hospital stay that lasts a minimum of 3 weeks. Intensity is progressive and adapted daily to individual capacities and feelings for each subject. Each session is composed of 3 sections: warm up, aerobic training and cool-down. Warm-up includes soft joint movements, muscular mobilisation and mild reinforcement and cardio-vascular activation. This warm-up aims at preparing to exercise and to prevent injury. The training consists in cycloergometer practice that includes endurance training and interval training. The cool-down period allows patients to rest and return to normal physiological parameters. This phase uses light stretching focus on inferior limbs, core and back and respiratory exercises (APA; EXER) or respiratory guided exercises (BIO).

In APA and BIO group, patients use classical stationary Cycloergometer (Domyos™ model 06 500). In EXER group, patients practice on an Expresso™ Go Straight device. The Expresso bike is an interactive and immersive device. This tool immerses users in different virtual environments. The changes in itinerary are applied to the bike in real time. For example, when a change in drop occurs, it is instantly reflected in the crankset. For each session, patients choose the landscape(s) in a preselectional list of 30 possibilities and under the APA instructor’s advices.

In the BIO group, subjects practice biofeedback relaxation guided exercises on displayed on a screen instead of the cool-down period. HRVB Training (HRVBT) consists in a minimal of 20 minutes session at the end of each physical exercise session with the Symbiofi™ Cardiac coherence software (SymbioCenter® technology, SymbioLine® Professional, SYMBIOFI, Loos, France). This device provides various interactive workouts to control the rhythm and amplitude of respiration. HRVBT aims to achieve a cardiac coherence state with an elevated cardiac coherence score. To help patients to achieve the cardiac coherence state, some indications (cardiac coherence score, adapted respiratory rhythm guide, HR, …) are displaying on the screen in real time. The feedback of HRV percentage in real time is also displayed on the screen. All the information come from a pulse sensor. First session is supervised by the APA instructor. It enables patients to familiarise themselves with the dispositive and HRVBT notions. The next sessions are conducted independently by the patients themselves (details are resumed in Table 1).

Table 1: Details of the programs

Assessments:

Anxiety and depression assessment:

Anxiety and depression are evaluated with the Hospital Anxiety and Depression Scale (HADS). This scale is commonly used in hospitals for oncological patients to detect anxiety or depression symptoms. This tool allows the measurement of anxiety and depression while differentiating somatic from physical symptoms and disorders⁶². Using HADS aims to complete the profile of subjects and detect potential anxious or depressive tendencies.

State of anxiety assessment:

The State and Trait Anxiety Inventory (STAI)³⁵, is used to evaluated anxiety in two different dimensions: State (YA) and Trait (YB). The APAER-H protocol only considers the YA dimension. State Anxiety is defined as the level of intensity according to a particular situation or context. The STAI-YA consists of 20 items. Patients are asked to answer each item on a Likert scale ranging from 1 to 4 (1- “not at all”, 2- “rather no”, 3- “rather yes” and 4- “completely yes”). The level of state anxiety is represented by a final score with a minimum value of 20 and a maximum of 80 points. A higher score indicates a high level of state anxiety.

Fatigue Assessment:

The French version of the Multi-Dimensional Fatigue–20 items (MFI-20) is used to evaluate the fatigue level⁶³. This version includes 4 dimensions: General/physical fatigue with 9 specific items, mental fatigue with 6 specific items, reduced activities with 3 specific items, and motivation with 2 specific items. Each item consists of a 1 to 5-points Likert scale ranging from “Yes, it’s true” to “No, it is not true”. The level of fatigue is represented by a final normalised score of 0-100. A higher score indicates a high degree of fatigue.

Physical fitness assessment:

Physical fitness is evaluated with 2 submaximal tests: the 2-Minute Walk Test (2MWT) and the Five-Times Sit to Stand Test (FTSST).

The 2MWT assesses the global functional capacity, cardiorespiratory capacity and physiological adaptation during physical exercise⁶⁴. Oxygen saturation (%) and heart rate (bpm) are monitored before, during and after a 2 minutes resting period to measure the cardiorespiratory adaptation during exercise and the effectiveness of recovery.

The FTSST evaluates global muscular abilities⁶⁵. Vital parameters are monitored as in the above test.

All of these assessments have been previously tested in hematologic patients or in the elderly. They are adapted and feasible for our study population^64,66.

Quality of life assessment:

Quality of Life (QoL) is estimated with the French validated version of the QLQC30 version 3.0 developed by the European Organisation for Research and Treatment of Cancer⁶⁷. The QLQ-C30 scores the level of individual QoL in different areas: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, nausea/vomiting, and pain); 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties); and a global health subscale. Scores are transformed to a 0–100 scale, with 100 reflecting highest functioning, highest symptomatology, or highest global health.

Activity of the immune system:

Results of blood sample analysis are collected. Leukocytes and neutrophils count (Giga/L), lymphocytes percentage (%) and inflammation markers (CRP; mg/L) are recorded from the samples taken during usual care.

Profile of Patients:

Each patient received a hematologist’s approval to APA practice. The APA instructor conducts an individual interview at the beginning of the program and, then collects relevant information about lifestyle habits, attitude to physical activity, objectives, expectations, and the needs of each patient. Before each session, the results of daily blood samples are checked to ensure the safety of physical practice. Indeed, high-dose treatments can significantly reduce bone marrow function. Consequently, patients often have very low platelets and haemoglobin levels. In that case, sessions are simply postponed or cancelled.

Satisfaction and adherence to the program:

Patients’ satisfaction and participation rates in APA sessions (including information about dropouts, cancelled or postponed sessions, and reasons for doing so) are monitored during the study to adjust the program or give some explanations about it at the end. Adherence and satisfaction are assessed through participants’ feedback and by comparing the number of planned sessions to the sessions actually performed.

Evaluation times and implementation:

First, the hematologist gives an introduction about the protocol, a medical prescription, and the consent form (T_− 1) to screened patients. Then, the APAER-H protocol includes 3 evaluation sessions: T1 at the beginning of the program, T2 at the program completion (hospital discharge) and T3 at the final assessment (1-month follow-up after hospital discharge) (Fig. 1). Details about it are presented in the Table 2.

For a proper conduct of the study, all staff are informed about the protocol and coordinated in their action.

The APA instructor assesses fatigue, state anxiety, and physical fitness (T0, T2). During the hospital stay, patients follow the APA program. Blood sample are analysed 4 times: on admission to hospital (Day 0), then at the beginning (Day 3 ± 2), middle (Day 10 ± 2) and end of the program (Day 21 ± 2). At program completion, the APA instructor provides recommendations and advice about daily APA practice and all the necessary information about it. One month after hospital discharge (T3), patients will be asked to complete the EORTC QLQ-C30 and return it by mail under anonymous conditions.

Randomisation and group assignment:

Double-blind or simple-blind designs are not allowed by the intervention. Randomisation is balanced across 3 parallel arms, with à 1: 1: 1 allocation ratio to maintain a high level of evidence. The Data Manager and Methodologist established the randomisation protocol before the study began to avoid predicable allocation. The randomisation list was imported into the CleanWeb module of Telemedicine Technologies SAS® electronic case report form (eCRF). Investigators use the eCRF for randomisation and data collection. The database was created using CleanWeb® software. Access is secured (personal ID and password required) with different levels of security based on the investigator’s role. Access is granted to hematologists and the APA instructor (with limited access to their respective outcomes). Meetings with Data-manager Centre are scheduled every 2 months during the study, and more if necessary.

Statistical analysis:

According to Chandwani et al., (2010)⁶⁸, we expect a decrease of 4 points with a standard deviation of 2.5 points in the STAI-YA score after the intervention. We anticipate differences in the STAI-YA scores among the groups: APA is expected to decrease by approximately 4 points, EXER by approximately 6 points and BIO by approximately 7 points, with SD of 2.5 points. With alpha level of 5% and a statistical power of 80%, we need to include 66 subjects (22 per group) to demonstrate a significant difference between groups. Due to an estimated 25% rate of missing data and dropouts (abandonment, early exit, death, etc.), we aim to include 90 patients in the protocol. They will be randomly assigned to one of three treatment groups (APA, n = 30; EXER, n = 30; BIO, n = 30).

ANOVA will be used to analyse the primary endpoint: state anxiety level and fatigue. The groups will be compared pairwise using Tuckey’s tests.

For the secondary criteria: depending on the distribution, Fischer’s test and ANOVA will be performed for qualitative and quantitative data, respectively (detailed are presented in Fig. 3). The significance level will be set at 5%. The analysis will be conducted on an intention-to-treat basis. A detailed analysis plan is defined and validated by the study's scientific advisory board.

Supportive care, including Adapted Physical Activity (APA), are currently being developed in oncohematology. Previous studies have investigated the feasibility and effectiveness of APA before, during, and after high-dose treatment in Hematological Intensive Care Units (HICU) on various parameters^4,7,9,25,29.

During HICU treatments, fatigue is one of the major reported symptoms²¹ and regular APA practice limits the increase in and severity of fatigue²⁵. Indeed, Wiskemann et al. (2011)³⁰, highlighted a 15% decrease in fatigue among individuals receiving a 12-weeks APA program (aerobic and strength training, 3 supervised sessions per week, associated with 2 autonomic sessions during inpatient and after hospital discharge). The APAER-H study aims at analysing whether a 3-weeks aerobic programs during HICU hospital stay only could be sufficient to mitigate fatigue to the hospital discharge. In addition to fatigue, functional capacities decline after HICU treatments. Together, they lead patient into the vicious circle of Cancer-Related Deconditioning. Adding APA practice helps to maintain or improve endurance, muscular strength and aerobic capacities. Jarden et al. (2009)²¹ put forward that APA practice could maintain muscular capacities in HICU patients. In the same study, the authors highlighted a 27.8% decrease in VO_2max at the end of an HICU stay whereas aerobic capacities remained similar in patients who practiced APA alongside treatments. Baumann et al. (2011)²⁵ demonstrated a similar effect on endurance capacity. To our knowledge, excepted Bryant et al. (2018)⁶⁹ who analysed the effects of an APA program during inpatient time for induction treatment in Acute Leukemia (AL) patients, all programs tested have longer duration than APAER-H protocol. Bryant et al, highlighted that a 4-week mixed-modality supervised exercise program in AL induction inpatient reduces fatigue but found no difference between groups in functional capacities. In their work, the authors proposed a 2 sessions per day including aerobic and resistance training (5 to 15 minutes and 10 to 20 minutes respectively). Only 17 patients (8 intervention and 9 control) could be involved in this study. APAER-H intervention consists in 3 aerobic sessions per week (stationary bicycle) at moderate intensity with a minimal duration of 30 minutes. Analysing the effects of a short APA program (3 weeks) on overall physical fitness and fatigue in a larger cohort (n = 90) is one of the aims of the APAER-H study.

Furthermore, the particular context of the HICU promotes the development of negative affects that can negatively influence physical and psychological well-being. Especially anxiety that increases during HICU treatments^{11, 31}. Anxiety is implicated in various mechanisms of cancer and immunity. To our knowledge, no study has stated on the effects of APA practice during HICU on anxiety yet. APA and relaxation are well known to reduce anxiety in some pathological populations^52,70. Determining and analysing the effects of APA practice on anxiety level during HICU treatments is the main objective of this study.

In a literature review, Fournié et al. (2021)⁵², have shown the benefits of HRVBT in chronic diseases. In another study, these same authors, focused on the hematological population⁷¹. They demonstrated the feasibility and effectiveness of HRVBT associated with APA practice on QoL, well-being, and anxiety in hematological patients 6 months after acute treatments. They highlighted that APA associated with HRVBT significantly improves physical capacities (overall capacity, cardio-respiratory, and muscular) and autonomic function (coherence ratio). The APAER-H study proposes to analyse the effects of APA associated with HRVBT in HICU patients during treatments. First, we aim to determine the effects of three 3-week aerobic programs on anxiety during this specific phase. Next, we aim to analyse the effects of APA associated with HRVBT on anxiety modulation during treatments in HICU compared to classic APA and Exergaming.

Previous studies have shown a high rate of adherence to APA practice in HICU, despite the many side-effects of treatments^9,69,72. Recent studies have demonstrated the effectiveness and added value of exergaming devices on the duration and adherence to practice^48–50. Da Silva Alves et al. (2017)⁷³ confirmed that exergaming practice is effective in lowering fatigue in cancer patients during and after treatments phases. Exergaming keeps patients entertained while exercising and it reduces their pain and worry⁷⁴. Moreover, it seems that a broader emotional experience is felt when bodies are involved in the game⁷⁵. In the same vein, Tsuda et al. (2016)⁷⁶ demonstrated that use of exergaming devices (Nintendo Wii™) is feasible and safe in older adults with haematological malignancies undergoing chemotherapy. Additionally, exergaming is an effective tool to maintain physical capacities⁷⁶. In the same study, the authors highlighted a decrease in anxiety levels measured by HADS post-intervention. To our knowledge, Schumacher et al. (2018)⁷⁷ are the only ones who have investigated the effect of exergaming on anxiety in HICU patients during treatments. They used a Nintendo Wii™ device and found a decrease in anxiety and depression levels and an increase in well-being. These findings suggest that exergaming could be an effective way to reduce anxiety in HICU patients. The Expresso device used in the APAER-H protocol could combine the effects of aerobic exercise with the fun of exergaming in an outdoor setting. In HICU, adding outdoor practice simulations and ludic exercises could be more effective on anxiety than APA alone but potentially less effective than APA associated with HRVBT. In this light, we also aim to determine if adding relaxation or exergaming devices could induce complementary or additional effects.

We pay particular attention to detail and describe the entire intervention with the hope of identifying modalities for an effective APA program in this particular context. We aim to facilitate implementation of supportive care, especially APA practice in HICU. The APAER-H protocol should help patients maintaining their physical fitness and improving their psycho-emotional states. Reducing anxiety levels should, also contribute to decrease inflammation. Therefore, regular APA helps patient to resist side effects more effectively and reduce the toxicity of chemotherapy high dose⁷⁸. These modifications could enhance the immune system and reduce inflammation^79,80. In this way, APA plays a role in reducing cancer relapse. Another axis of APAER-H study is to investigate the interactions between APA practice, inflammation and immune system activity. Additionally, we aim to determine if adding relaxation or exergaming could improve APA effectiveness on the level of fatigue and anxiety. Therefore, we hope to develop relevant knowledge about supportive care in cancer, especially concerning the psychophysiological parameters of HICU patients.

APAER-H: Adapted Physical Activity, Exergaming and biofeedback Relaxation in Hematological intensive care unit; HM: Hematological Malignancies; HSCT: Hematological Stem Cell Transplant; HICU: Hematological Intensive Care Unit; ADL: Acts of Daily Living; QoL: Quality of Life; APA: Adapted Physical Activity; HAS : Haute Autorité de Santé; WHO: World Health Organisation; INCa : Institut National contre le Cancer; CRP : C-Reactive Protein; ANS: Autonomic nervous system; HRVBT: Heart Rate Variability Biofeedback Training; HRV: Heart Rate Variability;

CHR: Centre Hospitalier Régional; HR: Heart Rate; HADS: Hospital Anxiety and Depression Scale; STAI: State-Trait Anxiety Inventory; MFI-20: Multidimensional Fatigue Inventory; 2MWT: 2min Walking Test; FTSST: Five Time Sit to Stand Test; QLQ-C30: Quality of Life Core Questionnaire; eCRF: Electronic Case Report Form

Acknowledgments

The authors wish to express their gratitude to Meunier Godelieve for supporting execution of this work. We are grateful to Leblanc Hugues for his technical advices and for critical comments on the manuscript. We also thank Salma Meraihi and Jérome Filiponne for their technical assistance.

Authors’ contributions

JB, CL, CG, AE-N, BB and VD contributed to the protocol design and wrote the

manuscript. JB, VD, GM contributed to the execution of experiments. All

authors have read and approved the manuscript.

Funding

This research is supported by the 2LPN laboratory of the University of Lorraine and by the Center Hospital of Metz-Thionville which fund the time dedicated to research activities, as well as by external funding from the Association Française des Malades du Myélome Multiple and Leucémie Espoir 57 which provided funding for the purchase of necessary equipment.

Availability of data and materials

After the completion of the current protocol, data and materials will be

available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

APAER-H protocol (version 1.1 of the 14/06/2022) was approved by the

French Sud Mediteranian III ethical committee and registered on ClinicalTrials.gov:

NCT05475600 (https://clinicaltrials.gov/).

Recruitment began December 2022 and the protocol is currently being conducted in the hematological Intensive care unit hematology unit of the Hospital Metz-Thionville.

Anticipated date of completion is January 2025. All patients will have to give their informed verbal consent (approved by the ethics committee) to participate in the study.

Consent for publication

Not applicable.

The authors declare that they have no competing interests.

Author details

¹ Lorraine Laboratory of Psychology and Neuroscience of Behavioral Dynamics (2LPN), University of Lorraine, UFR SciFA, Rue du Général Delestraint, 57070 Metz, France

²Clinical Research Department, Regional Hospital Center (CHR) of Metz-Thionville, Mercy Hospital, 1 allée du château, 57085 Metz Cedex 03, France

³ Hematology Department, Metz-Thionville Regional Hospital Center, Mercy Hospital, Metz 1 allée du château, 57085 Metz Cedex 03, France

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Adapted Physical Activity, Exergaming and Relaxation by biofeedback in Hematological intensive care unit – Study protocol of a Randomised Controlled Trial (APAER-H trial)

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Figures

BACKGROUND

Adapted Physical Activity & Hematological malignancies:

APA and Anxiety:

APA and Fatigue:

APA, Immune System & Inflammation factors:

Exergaming:

Relaxation: Heart Rate Variability Biofeedback Training

OBJECTIVES AND HYPOTHESIS:

METHODS AND DESIGN

Study population

Interventions:

Assessments:

Anxiety and depression assessment:

State of anxiety assessment:

Fatigue Assessment:

Physical fitness assessment:

Quality of life assessment:

Activity of the immune system:

Profile of Patients:

Satisfaction and adherence to the program:

Evaluation times and implementation:

Randomisation and group assignment:

Statistical analysis:

DISCUSSION

Abbreviations

Declarations

References

Table 2

Additional Declarations

Supplementary Files

Status:

Version 1