Authors: xiaoli Xu, Qiong Han, Zhipeng Yan, Jun Ni, Zhiyong Wang
Categories: Rehabilitation Medicine, Clinical Trial, Randomized Controlled Trial, Respiratory Therapy, Stroke Medicine, Protocol, 1727, 1506
Source: BMJ Open
Respiratory dysfunction is a notable complication in stroke patients, in which the diaphragm, as the primary respiratory muscle, directly influences lung function. Repetitive peripheral magnetic stimulation (rPMS) is a new, non-invasive approach that is used to treat brain and nerve problems. Few studies have examined the effect of magnetic stimulation on the phrenic nerve, breathing and diaphragm in stroke patients. This study aims to assess the effect of magnetic phrenic nerve stimulation on respiratory muscle function and lung function in adults with stroke. The results of this study may provide a promising approach to managing respiratory dysfunction in stroke patients.
This randomised controlled trial is designed to compare the effectiveness of bilateral magnetic phrenic nerve stimulation (rPMS) and conventional rehabilitation training in enhancing respiratory muscle strength, lung function indicators, diaphragmatic excursion and diaphragm thickness in patients with respiratory muscle weakness. Thirty patients admitted to the First Hospital of Fujian Medical University will be included in this study. Participants in the intervention group will undergo daily bilateral magnetic phrenic nerve stimulation for 2 weeks. Stimulation will be administered at a frequency of 25 Hz, with a pulse duration of 1.1 s and an inter-pulse interval of 5.9 s, for 5 days each week. Primary outcome measures will be assessed at baseline and after 2 weeks (end of the intervention) to evaluate the efficacy of rPMS compared with conventional rehabilitation techniques.
Before commencing the study, all participants will receive a comprehensive explanation of the study procedures, including the assessments. They will also be provided informed consent forms for review, completion and signing. This study was approved by the Ethics Committee for Research at the First Affiliated Hospital of Fujian Medical University (No.: MRCTA, ECFAH of FMU [2021]641, dated 10 November 2023) (Appendix Ⅰ & Ⅱ). The trial protocol will strictly adhere to the Uniform Standards for Reporting of Trials (CONSORT) statement. The trial has been registered with the Chinese Clinical Trial Registry.
Dissemination of individual findings for each participant will be available at the end of the study. The findings will be disseminated to different interest groups, participants or other patients with respiratory dysfunction through journal papers and/or conference presentations. The results of the primary trial will be submitted for publication in a peer-reviewed journal.
ChiCTR2300075669, registered on 12 September 2023.
Keywords: Clinical Trial, Respiratory Therapy, Randomized Controlled Trial, Stroke Medicine
According to a recent comprehensive study, the estimated lifetime risk of stroke for individuals aged ≥25 years is approximately 25% worldwide, regardless of the sex.^1^ Stroke exerts a substantial impact on both mortality and disability rates, ranking as the second leading cause of death globally and occupying the highest position in China.^2^ Respiratory dysfunction is a prevalent and significant complication observed in stroke patients, who may encounter a range of dysfunctions resulting from stroke.^3^ The diaphragm, which is the primary respiratory muscle, directly influences respiratory function. In stroke patients, the prevalence of diaphragmatic dysfunction is as high as 51.7%.^4^
Central nervous system damage in stroke patients can result in diaphragmatic atrophy,^5^ leading to reduced thickening capacity and shortening of the offset hemidiaphragm on the affected side.^6^ Moreover, stroke patients often exhibit significant weakness in both inspiratory and expiratory respiratory muscles.^7^ This weakness affects the volume of the chest cavity, chest wall and abdomen on the affected side and elevates the diaphragm,^8^ resulting in respiratory muscle weakness and cough dysfunction. This, in turn, increases the risk of pneumonia.^9^ Pulmonary infection is the most common complication in stroke patients, contributing to death in up to 30% of patients before hospital discharge.^10^ Furthermore, Janusz et al highlighted that stroke-induced respiratory muscle weakness has an additional detrimental effect on a patient’s sense of balance and other motor functions,^11^ thereby exacerbating the challenges inherent to the rehabilitation process.
Inspiratory muscle training is an effective intervention for improving lung function and cardiorespiratory endurance and reducing the occurrence of pulmonary infections in post-stroke individuals.12,14 A meta-analysis yielded moderate-quality evidence supporting the beneficial effects of inspiratory muscle training on exercise tolerance, diaphragmatic thickness and short-term lung function (specifically, PEF) in stroke survivors.^15^ Notably, all the above methods require full cooperation from the patient. However, the effectiveness of the intervention may be affected by the patients’ reduced comprehension and poor cardiorespiratory endurance after stroke. According to recent recommendations from the official ATS workshop report, a new approach for pulmonary rehabilitation is needed.^16^Therefore, active and effective treatment of patients with respiratory muscle weakness after stroke is urgently needed to address the key to rehabilitation.
Non-invasive extracorporeal neuromodulation technology has recently gained prominence as a promising treatment modality, drawing increasing attention in the field of rehabilitation and in the broader medical community. One notable technique is repetitive peripheral magnetic stimulation (rPMS) therapy, which offers an innovative and non-invasive approach to neurorehabilitation. rPMS can effectively address brain or nerve-related impairments, thereby improving limb function and restoring motor capabilities with minimal adverse effects.^17 18^ Given these unique advantages, rPMS is becoming increasingly prevalent in clinical practice. Spiesshoefer et al^19^and Jung et al^20^ used rPMS to evaluate diaphragm function. They generated motor-evoked potentials and compound muscle action potentials by magnetically stimulating the phrenic nerve in the cortex and neck.
Notably, research on the use of rPMS in respiratory rehabilitation remains limited, with previous studies primarily focusing on the assessment of diaphragmatic function without direct phrenic nerve stimulation to activate the diaphragm. Recent studies have indicated that rPMS-induced muscle activation occurs through nerve stimulation, which acts on intramuscular motor axons and induces muscle contractions. Subsequent synergistic contractions result from depolarisation of the terminal motor nerve branches.^21^ Given that diaphragmatic movements are closely linked to motor function,^22^ we hypothesised that phrenic nerve stimulation through rPMS could enhance diaphragmatic function in stroke patients, thereby improving respiratory performance. This study aimed to investigate the effects of 2 weeks of magnetic phrenic nerve stimulation on respiratory function in individuals who have suffered a stroke.
This study will be a parallel controlled randomised trial comparing the effects of rPMS applied to the bilateral phrenic nerves in the neck with those of conventional rehabilitation for respiratory function in stroke patients. Baseline assessments will be conducted 1–3 days before initiating the intervention, and post-intervention assessments will be performed 1–3 days after the conclusion of the intervention. An assessor responsible for safeguarding randomisation and intervention confidentiality will conduct these assessments. The detailed procedure and flow diagram are presented in table 1 and figure 1, respectively.
Figure 1 The study’s flowchart.
Patient and public involvement was not included in the development of this research protocol. However, all participants will receive a copy of their personal results on completion, as well as a copy of the final study results when they become available.
Thirty patients will be recruited for this study from the Department of Rehabilitation Medicine of the First Affiliated Hospital of Fujian Medical University.
Participants who fail to participate in the post-test, miss two consecutive intervention sessions or experience any change in medication dose or type that could potentially impact the study outcome will be considered as dropouts. However, participants will retain the option to voluntarily withdraw from the study at any time. During the initial baseline assessment, the researchers will obtain participants’ consent to maintain contact in the event of study discontinuation. This will allow us to conduct an accurate intention-to-treat analysis of the primary outcomes.
After informing families and patients about the study and obtaining their consent to participate, they will be asked to sign a consent form (online supplemental appendix 3). Following enrolment, randomisation will be computer-based and conducted at a 1 ratio according to a random sequence generated in REDCap, stratified by age (< or ≥50 years) and sex (female or male). The details of the allocation will be kept confidential for those involved in the assessment. Access to randomisation data in REDCap will be restricted to project management. The allocation information will be then communicated by the project manager to the physiotherapist in the ward, who will relay it to the patient. Assessors and statisticians will be blinded to the treatment group allocation. Patients will be treated individually and will not be made aware of the study hypothesis. Open blinding will not be allowed. However, owing to the nature of the treatment, blinding of patients will be not possible. Patients will receive individualised treatment and remain unaware of the study hypothesis. No planned circumstances have been established for unblinding.
Patients in both groups will be permitted to continue pharmacological treatment without interruption during the study and undergo standard rehabilitation, including postural training, motor training, respiratory control, enhanced coughing technique, chest wall mobility, oral exercises, Mendelssohn manoeuvre, effortful swallowing and supraglottic manoeuvres. In the experimental group, patients will receive bilateral phrenic nerve magnetic stimulation for routine respiratory function exercises. The transcranial magnetic stimulation will be performed using a circular coil with a diameter of 6.0 cm (YRD-CCY1; Wuhan Iridium Medical Equipment New Technology Co.).
The intervention will begin with a 3 min resting period to establish baseline measurements. Subsequently, diaphragmatic excursion will be visualised using ultrasound. Initially, the coil will be positioned at a location that elicits the most significant diaphragmatic movement in response to a single stimulus. Final adjustments will be made to the coil’s position to minimise excessive arm and head movements during magnetic stimulation, thus determining the optimal stimulation position. All rPMS procedures will be conducted with the patient positioned in a hospital bed tilted upright at a 30° elevation of the trunk. A vacuum pad will be used to support the patient’s head, creating slight neck extension. Anatomical landmarks will be meticulously documented to maintain consistent head and body positioning throughout all stimulations, ensuring precise reproducibility of body position during subsequent visits.
In the intervention group, after coil placement, a single stimulation will be administered at a frequency of 25 Hz, beginning with the initial stimulator output set at 5% of the maximum value. The output will be increased in 2% increments until the patient reaches the tolerance limit, thereby determining the stimulation frequency for the patient.^23 24^ To prevent diaphragmatic fatigue, the affected phrenic nerve will be stimulated in the morning, and the healthy phrenic nerve will be stimulated in the afternoon, with each session lasting for 10 min. The magnetic stimulator will be set to deliver stimulation at a frequency of 25 Hz, with a stimulation time of 1.1 s and a stimulation pause time of 5.9 s, resulting in the generation of 27 pulses with each tidal breath.^24^At the end of the intervention period, routine respiratory rehabilitation will take place after a 3–5 min break. This training regimen will be administered before a meal, 5 days a week, for a duration of 2 weeks.
On completion of the study, participants will receive RMB 300. Additionally, they will receive a personalised report summarising their performance in pre- and post-intervention assessments. Furthermore, every treatment session will be overseen by a proficient physiotherapy researcher to ensure the high-quality execution of machine operations and rehabilitation exercises.
Measurements will be taken on two initially at baseline (pre-treatment) and after a 2 week period (post-treatment), following the conclusion of the training programme. The effectiveness of the training programme will be assessed by the same physiatrist who will remain unaware of the specific type of training programme to ensure an unbiased evaluation of any observed changes (table 1).
Maximum inspiratory pressure (MIP) is the maximum inspiratory oral pressure that can be produced by inspirating with maximal effort in the functional residual breathing position or residual breathing position and airway obstruction, which responds to the comprehensive inspiratory force of all inspiratory muscles. It is currently an important non-traumatic index to assess the function of inspiratory muscles. If MIP falls below 30% of the predicted value, respiratory failure is likely to occur.
Maximum expiratory pressure (MEP) is the maximum oral pressure that can be generated with maximal effort expiration in terms of TLC and airway obstruction. It represents the combined expiratory power of all the expiratory muscles.
This study will use a portable pulmonary function tester-X1 (Seker (Xiamen) Medical Devices Co.) to detect MIP and MEP. Patients will be tested for MIP and MEP in a sitting position.
The standard spirometry method will be used to perform lung function tests on participants in a sitting position. The main observables will include forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, peak expiratory flow (PEF) and maximal voluntary ventilation (MVV), which will be measured using a Nanjing Hanart Cardiopulmonary Exercise Function Tester (Smax58ce-sp).
An ACUSON NX3 Elite colour Doppler ultrasound diagnostic system connected to a 6–13 MHz line array transducer will be used to assess diaphragm thickness (DT) and diaphragm thickening fraction. Patients’ bilateral diaphragmatic motion will be assessed using a 3.0–5.5 MHz transducer. Participants will be instructed to lie flat on a treatment bed with their head elevated by 30° for diaphragmatic ultrasound assessment.
Using GPower software (version 3.1.9.7, Germany), the sample size for each group was calculated based on two previous studies,^13 25^ and the effect sizes of MIP were 1.02 and 1.6, respectively, with a mean of 1.31. The test power was set to 0.85, the alpha error probability was 0.05 and the total sample size for the study was 30, with a 20% sample dropout rate. The ratio of the rPMS to control group was 1, and we verified the adequacy of the sample size of 30 populations using the statistical software GPower, which showed a statistical power of over 99% with a significance level (p value) of less than 0.05 (online supplemental appendix 4).
Data analysis will be conducted using statistical software packages, including R and Free Statistics software, and the normality of variables will be assessed using the Shapiro–Wilk test. Normally distributed continuous variables will be reported as mean±SD, along with 95% CIs. Median and IQR will be used for non-normally distributed continuous variables. Categorical variables will be presented as absolute frequencies and percentages.
To compare the groups, we will conduct a two-way repeated measure analysis of variance using GraphPad Prism 5. Subsequently, we will employ Bonferroni’s post-hoc test to account for multiple comparisons. A significance level of 5% (p<0.05) will be applied. In the case of paired samples, we will use the Student’s t-test for parametric data and the Wilcoxon test for non-parametric data to compare results before and after the intragroup intervention, as appropriate, based on data distribution. To quantify the effect size, Cohen’s d will be computed. We will perform a regression analysis, adjusting for confounding variables such as age and the time elapsed from stroke to the baseline assessment.
An intention-to-treat analysis will be conducted to ensure the inclusion of all randomised participants. Thus, participants will be analysed within their allocated groups, regardless of their adherence to the intervention protocol (reassessment of all patients will be scheduled). If this method proves impractical, we will employ multiple imputation to handle missing data.
Each participant will be assigned a unique code to identify their data and biospecimens. Personal identifiers such as names, email addresses and phone numbers will be securely stored in a password-protected computer database that will be accessible only to the researchers. Because the sample size is relatively small (n=30) and there are no known adverse events, a formal data monitoring committee will not be required.
Although independent trial auditing is not planned, any missing data will be diligently addressed using REDCap. Additionally, protocol procedures will be continuously discussed and evaluated by the assessors and physiotherapists responsible for rPMS implementation.
All data will be securely stored at the First Affiliated Hospital of Fujian Medical University for 15 years, after which the data will be destroyed.
Any deviation from the proposed protocol will be communicated by updating the ClinicalTrials.gov registry and by a letter to the editor of the journal.
Any adverse events that occur during the study will be recorded in REDCap, and the project manager will be notified immediately by the staff. The project manager will then work with the patient and physiotherapist to determine the appropriate course of action. Because participants in this project are hospitalised, they have the right to seek compensation in case of any unforeseen incidents related to rPMS. Adverse events leading to participant withdrawal will be reported in future publications. It is important to note that no formal analysis of adverse events is planned.
This study was organised and coordinated by the Research Department of the Department of Rehabilitation Medicine at the First Affiliated Hospital of Fujian Medical University. The participants were clinicians and researchers from the Department of Rehabilitation Medicine, the First Affiliated Hospital of Fujian Medical University. All parties participated in the steering committee and made the final decisions regarding the implementation plan.
This study represents the first investigation of the effects of phrenic nerve magnetic stimulation on respiratory function and other clinically significant outcomes in stroke patients. The primary aim of this study is to assess the influence of phrenic nerve stimulation on respiratory function in stroke patients who exhibited a decline in MIP and MEP. The secondary aims to evaluate the impact of phrenic nerve magnetic stimulation on pulmonary function, DT and mobility.
The results of this study will indicate that phrenic nerve stimulation can facilitate diaphragmatic contraction, thereby enhancing respiratory function in patients, potentially facilitating earlier rehabilitation and enabling them to engage in daily activities sooner.^13^ Historical respiratory rehabilitation interventions usually last for 6–8 weeks.^12 13 26 27^ Considering the customary rPMS intervention period, which typically spans 1–3 weeks in clinical practice,28,30 and accounting for the average length of hospitalisation of our patients, we established a 2 week intervention timeframe to ensure completion within the hospital stay.
We believe that exploring whether shortening the intervention time can effectively affect patients’ respiratory function and improve their ability to participate in rehabilitation exercises and daily activities is important. Additionally, this study is easy to implement, and patient cooperation is expected to be good, which should increase the feasibility of the study. This study will involve a significant number of stroke patients with sensory and motor impairments regardless of stroke severity. Therefore, it will help in developing interventions that are crucially beneficial for patients with severe injuries.
The researchers chose not to use sham phrenic nerve magnetic stimulation in the control group because of the fatigue and burden experienced by patients who undergo this procedure. This decision aligns with ethical principles that prioritise patient well-being and responsible resource use. In summary, this study presents a novel method for exploring the potential of phrenic nerve stimulation to enhance respiratory function in stroke patients. This study has the potential to expand our current knowledge base and provide physical therapists with practical insights for improving patient treatment.
This trial was registered under the number ChiCTR2300075669 on 12 September 2023. Enrolment is currently in progress, and recruitment is anticipated to commence on 13 September 2023, with completion expected by 13 September 2025. This trial adheres to the SPIRIT checklist (Additional File 1). Protocol version 2 (1 December 2023).
We express our sincere appreciation to all the contributors for their invaluable assistance in conducting this study.
Data sharing not applicable as no datasets generated and/or analysed for this study.