Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults: study protocol for a randomized controlled trial

Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults: study protocol for a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults: study protocol for a randomized controlled trial Xiang Li, An Yu, Liuyan Wang, Mei Xie, Xi Chen, Rui Li, Ying Gao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5800105/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background: Multimorbidity (≥2 co-existing conditions in an individual), especially co-existing essential hypertension (EH), type 2 diabetes mellitus (T2DM), and hyperlipidemia two or above, is a major global health challenge with substantial impact on individuals, carers and society. This trial aims to examine the efficacy of integrating low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) into the management of multimorbidity (co-existing EH, T2DM, and hyperlipidemia two or above) in older adults and explore the underlying mechanisms through which Lo-TENS may alleviate the clinical indicators of multimorbidity, providing insights into its potential value as a novel adjunctive treatment modality. Methods: This prospective, randomized controlled trial (RCT) will enroll 50 older adults with multimorbidity, and randomly assign them to one of the two groups: 1) Lo-TENS plus routine clinical management group; or 2) sham stimulation plus routine clinical management group. Participants in each group will receive their respective stimulation one 30 min session/day, 5 days/week, for 4 consecutive weeks. The primary outcomes of interest are blood pressure, blood sugar and blood lipid, with secondary outcomes encompassing heart rate variability and various biochemical indicators. Comprehensive assessments will be performed at baseline, immediately post-intervention, and at 4-week follow-up. Discussion: This trial will provide evidence on the effectiveness of Lo-TENS on clinical outcomes in multimorbidity in older adults, and decipher the working mechanisms of Lo-TENS to multimorbidity. Trial registration: Chinese Clinical Trial Registry Platform: www.chictr.org.cn (No. ChiCTR2400093956). multimorbidity essential hypertension type 2 diabetes mellitus hyperlipidemia transcutaneous electrical nerve stimulation study protocol randomized controlled trial Figures Figure 1 Figure 2 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults Trial registration {2a and 2b}. Chinese Clinical Trial Registry reference: www.chictr.org.cn (No. ChiCTR2400093956) Trial Registration Data Set of this trial is not relevant to World health organization Protocol version {3} First version Funding {4} Kunming Health Science and Technology Talent Training Project, Kunming Geriatric Syndrome Rehabilitation Treatment Medical Technology Center [No. 2023-SW (Technology)-26]. Author details {5a} Xiang Li 1 , An Yu 2 , Liuyan Wang 1 , Mei Xie 1 , Xi Chen 1 , Rui Li 1 , Ying Gao 1 , Bijuan Liang 3 , Qi Wu 3 , Wei Zhang 4* , Lei Yang 1 * 1 Department of Rehabilitation Medicine, The Second People’s Hospital of Kunming, Kunming, Yunnan, China 2 Yunnan Key Laboratory for Basic Research On Bone and Joint Diseases, Kunming University, Kunming, Yunnan, China 3 Department of Geriatrics, The Second People’s Hospital of Kunming, Kunming, Yunnan, China 4 Department of Rehabilitation Medicine, Yan An Hospital of Kunming City, Kunming, Yunnan, China Name and contact information for the trial sponsor {5b} The provision of trial sponsor contact information is not applicable to our research. Role of sponsor {5c} The sponsor played no part in study design, collection, management, analysis, and interpretation of data, writing of the report, or the decision to submit the report for publication. Introduction Background and rationale {6a} A primary challenge in the traditional clinical management of the older adults stems from the concurrent presence of multiple chronic conditions, or multimorbidity, which often span across different organ systems and discipline-based boundaries [1,2]. Conditions such as essential hypertension (EH), type 2 diabetes mellitus (T2DM), and hyperlipidemia are common examples [3-5]. Multimorbidity is increasingly becoming the norm rather than the exception among older adults [1,6]. The rate of multimorbidity rises significantly with advancing age [3,4], affecting 55% to 98% of the elderly population [5,6]. Compelling evidence indicates that individuals with multimorbidity are at a higher risk of premature mortality [5,6], have an alarming 99-fold increased likelihood of hospitalization for ambulatory care-sensitive conditions, and experience more rapid functional decline and higher disability rates [7,8]. Additionally, they are more prone to reliance on long-term care, tend to report a lower quality of life and incur significantly higher healthcare costs [9,10]. Although numerous guidelines on the clinical management of multimorbidity have been published [11,12], the effective implementation of these guidelines is often hindered by the overlay of multiple conditions as well as the adverse events and/or the drug interactions associated with polypharmacy [13], leading to an unsatisfactorily low level of multimorbidity management [14,15]. Subsequently, escalating research endeavors have been oriented towards uncovering alternative strategies to optimize multimorbidity management outcomes within the older adults [16]. Research has demonstrated that sympathetic over-activation is prevalent among individuals with essential EH, T2DM, and hyperlipidemia, playing a pivotal role in the initiation, perpetuation, and progression of these diseases [17-21]. These findings have given rise to the neurogenic hypothesis of common chronic diseases in the elderly, underscoring the potential pathophysiological significance of sympathetic neural abnormalities [22,23]. Considering the adverse effects of sympathetic over-activation, it is plausible that alleviating sympathoexcitation could provide clinical benefits in managing morbidity in older adults. Stein et al. discovered that in healthy subjects, low-frequency (2 Hz) transcutaneous electrical nerve stimulation (Lo-TENS) can reduce sympathetic nervous system activity and enhance parasympathetic nervous system activity, while high-frequency (100 Hz) TENS increases sympathetic nervous system activity when applied to the paravertebral ganglion regions [24]. Moreover, TENS is recognized for its cost-effectiveness, self-administration feasibility [25], and minimal side effects compared to other treatment modalities, positioning it as a promising alternative or adjunct to current standard therapies in the management of common chronic diseases [26]. Objectives {7} To the best of our knowledge, no research has yet assessed the impact of Lo-TENS on the management of multimorbidity in older adults. This randomized controlled trial is thus designed to examine the efficacy of integrating Lo-TENS into the management of multimorbidity (EH, T2DM, and hyperlipidemia) in this demographic. This study hypothesizes that the incorporation of Lo-TENS as an adjunct therapy will enhance multimorbidity management outcomes in the older adults, surpassing the effects of traditional clinical management alone. Trial design {8} This study will employ a prospective, single-blind, parallel-group, randomized controlled clinical trial design. Following the initial baseline assessment, participants will be randomly allocated to one of the two arms: 1) the Lo-TENS plus routine clinical management group; or 2) the sham stimulation plus routine clinical management group. Figure 1 illustrates the trial’s flow diagram. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is detailed in Appendix I. Methods: Participants, interventions, and outcomes Study setting {9} The study setting will be in The Second People’s Hospital of Kunming. Eligibility criteria {10} The inclusion criteria for this study are as follows: Participants must be aged between 60 and 80 years; They must have co-existed two or more of the following chronic conditions: EH, T2DM, and hyperlipidemia, for at least one year; Participants must be medically stable; They must be capable of understanding and following 3-step commands; Participants must have provided signed informed consent. The exclusion criteria include: Contraindications to electrical stimulation therapy, such as the presence of a cardiac pacemaker, metal implants, skin conditions affecting the treatment area (e.g., scratches, inflammation), or a history of epilepsy or tumors; Use of medications, other than routine therapy for managing co-existing chronic diseases, that affect blood pressure, blood sugar, and/or lipids within the past two months (e.g., glucocorticoids, central nervous system inhibitors); Severe cognitive or speech impairments that would interfere with study participation; Other serious illnesses that could influence blood pressure, blood sugar, and/or lipids; Participation in another clinical trial within the past two months. Who will take informed consent? {26a} Professional rehabilitation therapists will provide a comprehensive explanation of the trial to potential participants. Should participants express a willingness to participate, the therapist will then proceed to obtain their signature on the informed consent form. Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable. No additional consent provisions are required for the collection and utilization of participant data and biological specimens within the scope of this trial. Interventions Explanation for the choice of comparators {6b} Blood pressure, blood sugar, and lipid levels are susceptible to influences from various factors, including medication, exercise, and mobility, among others. Consequently, a sham stimulation is employed in this study to discern whether observed changes in these health indicators are due to external factors or the actual treatment stimulation. Intervention description {11a} The stimulation protocol for both groups was meticulously designed in accordance with the research intervention description of the TIDieR (Template for Intervention Description and Replication) template [27], with specific details outlined in Table 1. Participants in each group will undergo their assigned stimulation in one 30-minute session per day, over a period of 5 days per week, for a total of 4 consecutive weeks (resulting in 20 sessions in total). To ensure the blinding process, the stimulation sessions for the two groups will be held in separate physical agent therapy rooms, preventing participants from discussing their experiences with the stimulation. Throughout the stimulation period, participants will be closely monitored and supervised to ensure their safety and to minimize the risk of emergencies or adverse events. Lo-TENS Participants will be seated in a comfortable chair. Prior to the application of low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) therapy using the KD-2A device from Yaoyang Kangda Electronic Instrument Co., Ltd in Beijing, China, the skin will be thoroughly cleaned. A self-adhesive electrode plate measuring 5 x 5 cm will be affixed to the dorsal aspect of the first and second metacarpal bones. An additional electrode plate will be positioned over the muscle belly of the proximal radius, with both upper limbs receiving the placement (refer to Figure 2). The stimulation parameters are set as follows: mode, continuous; waveform, bidirectional asymmetric square wave; pulse width, 200 μs; frequency, 2 Hz. The stimulation intensity in milliamps (mA) will be tailored to the individual’s sensation, permitting slight muscle contraction but ensuring that pain or any discomfort is avoided. Sham Stimulation Participants in the control group will receive the sham stimulation, i.e., only the electrodes are placed, and the stimulation parameters are the same, but no actual treatment. Routine clinical management Participants in both groups will take their regular medications to control their multimorbidity. Criteria for discontinuing or modifying allocated interventions {11b} While low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) is inherently safe, should participants experience any irreversible stimulation-related adverse events such as nausea, dizziness, disorientation, postural instability, or fatigue during the trial, their participation will be discontinued immediately to ensure their well-being and safety. Strategies to improve adherence to interventions {11c} The following measures will be taken to achieve the best intervention adherence: 1. The intervention schedule of the participant can be adjusted according to the actual availability of time of the day. 2. Close attention is always given to the feedback of participants during stimulation. 3. Participants’ medications, exercise, and mobility levels will be assessed weekly; and 4. Participants’ decision to withdraw from the trial will be supported. Relevant concomitant care permitted or prohibited during the trial {11d} Not applicable. No limitations are imposed on concurrent care throughout the duration of the trial. Provisions for post-trial care {30} Not applicable. Ancillary and post-trial care provisions are considered unnecessary for the current study design. Additionally, no compensation for trial participation is planned, as the trial is not expected to cause any harm to participants. Outcomes {12} Comprehensive demographic information, including age, gender, type of diseases, onset time, and medication details, will be gathered during the initial baseline assessment. Outcome measurements will be conducted by an assessor who is unaware of the treatment allocation on three separate occasions: initially at baseline, following the intervention’s completion, and at the 4-week follow-up point (as detailed in Table 2). Primary outcomes Office blood pressure: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be measured using an electronic sphygmomanometer (HEM-7136, Omron Corporation, Kyoto, Japan). Participants will be instructed to remain at rest for a minimum of 5 minutes. Subsequently, SBP and DBP will be measured on both arms, while the participant is seated and the measuring arm is positioned at heart level [28]. The arm with the higher SBP will be designated as the research arm. The blood pressure will be measured three times at 5-minute intervals, and the average of the three readings will be recorded [29]. Fasting blood glucose (FBG): After waking up in the morning and fasting for more than 8 hours without consuming any food, medication, or insulin, check the blood sugar levels. Low-Density Lipoprotein Cholesterol (LDL-C): Often referred to as "bad" cholesterol because high levels can lead to plaque buildup in the arteries, increasing the risk of heart disease and stroke. Triglycerides: Triglycerides are a type of blood fat that serves as the primary source of energy for the body. Elevated triglyceride levels are associated with an increased risk of heart and vascular disease, including heart attack and stroke. Very high triglyceride levels can cause acute inflammation of the pancreas, known as pancreatitis. This condition can be severe, painful, and potentially life-threatening. Secondary outcomes Sympathetic nerve activity : A 24-hour ambulatory electrocardiogram (ECG) system (model ER1, Shenzhen Yuandong Innovation Technology Co., Ltd., Shenzhen, China) will be utilized to capture the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz) components of participants’ heart rate and heart rate variability (HRV). From these recordings, the sympathetic-vagal index (LF/HF ratio) will be derived to assess sympathetic nerve activity. The LF/HF ratio will be categorized as low, moderate, or high, with threshold values set at 0.2, 0.5, and 0.8, respectively [30]. Participants are instructed to carry out their regular daily activities throughout the 24-hour ECG monitoring period. All collected data will be digitally stored on a computer and subsequently analyzed by a trained analyst. 24-hour blood pressure: A 24-hour ambulatory blood pressure monitor (ABPM) (SY-B-003, Hunan Saihong Medical Technology Co., Ltd., Changsha, China) will be used to collect data on the mean, standard deviation, maximum and minimum values of patient’s all-day systolic, diastolic blood pressure, mean arterial pressure, and pulse pressure. Blood test: Peripheral blood of the participants will be extracted by the experienced nurses, and the concentrations of plasma glucose, glycosylated hemoglobin (HbA1c), insulin, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) will be measured by the laboratory department in the hospital. Biochemical indicators: The peripheral blood will also be used to assess the following indicators: C-reactive protein (CRP), adiponectin, tumor necrosis factor-α (TNF-α)，fibroblast growth factor 21 (FGF21), and norepinephrine, IL-6, IL-1β, IL-11. Participant timeline {13} Timeline for participants’ enrolment, interventions, and assessments is shown in Table 2. Sample size {14} Sample size estimation for our study was conducted using G*Power 3.1 software (Heinrich-Heine-Universitat, Dusseldorf, Germany). Given the three primary outcome measures in our study—blood pressure, glycemia, and lipid levels—it was essential to approach sample size estimation comprehensively. For blood pressure, a study by Tu et al. reported that after a 12-week intervention, Lo-TENS led to a significantly greater reduction in systolic blood pressure (SBP) compared to maintaining medication and health education, with a Cohen's d effect size of 0.93 (equivalent to f=0.465) [31]. In the case of glycemia, a study by Lu et al. investigated the effects of Lo-TENS on individuals with T2DM. They found that after a 20-week intervention, the Lo-TENS group experienced a significantly greater reduction in fasting plasma glucose (FPG) compared to the placebo group, with a Cohen's d effect size of 0.565 (equivalent to f=0.282) [32]. For lipid levels, Wu et al. demonstrated significant reductions in total cholesterol (TC) and triglycerides (TG) after an 8-week intervention, with Cohen's d effect sizes of 1.286 and 1.327 (equivalent to f=0.643 and 0.663), respectively [33]. Considering these findings, we adopted the smallest effect size (f=0.282) from the Lu et al. study for our sample size calculations. Additionally, our trial features a shorter intervention period of 4 weeks and does not include lifestyle modifications, exercise programs, or diet management as part of the intervention. Based on a 2 × 3 analysis of variance (ANOVA), assuming a medium effect size (f=0.2), an alpha level of 0.05, a power of 0.80, and an attrition rate of 20%, the estimated sample size required is 50 participants in total, with 25 participants per group. Recruitment {15} Participants in the study will be enrolled in The Second People's Hospital of Kunming. The research team will initially conduct a screening process to determine the eligibility of potential participants. Throughout the follow-up period, patients will be kept informed about the research’s progress and will be provided with updates on their individual results. Additionally, researchers will maintain ongoing communication with the physicians overseeing the care of each participant. Upon the study's conclusion, both the medical professionals and patients will receive a comprehensive final report detailing the outcomes. Assignment of interventions: allocation Sequence generation {16a} The study investigator will use the online tool (www.randomization.com) to generate the randomization sequence. Concealment mechanism {16b} Treatment allocation will be concealed in an opaque envelope from the study investigator and kept closed until the baseline assessment is completed by a blinded assessor. Implementation {16c} The principal investigator will assign participants to one of the two groups according to the randomization sequence. Assignment of interventions: Blinding Who will be blinded {17a} Participants will be blinded to the stimulation condition (real stimulation or sham stimulation), and told that “the skin sensation induced by electrical stimulation is very little”. Procedure for unblinding if needed {17b} Not applicable. Emergency unblinding to our trial is not applicable because it is impossible to blind the therapist in our trial. Data collection and management Plans for assessment and collection of outcomes {18a} To ensure the quality and integrity of the research prior to the trial's commencement, we will conduct comprehensive training for all involved personnel and verify the functionality of all relevant equipment. The steps we will take include: Ensuring that the recruiting physicians have a thorough understanding of the experimental procedures; Training physical therapists in the precise execution of the intervention program, as well as in the management of any potential adverse events that may occur during stimulation; Providing assessors with training on the proper collection and processing of outcome measures. Plans to promote participant retention and complete follow-up {18b} A follow-up assessment will be scheduled four weeks post-intervention. Participants will be contacted via telephone and invited to return to the hospital for this assessment. Data management {19} The Safety Supervision Committee from the participating hospitals will have overall oversight of this project. They will be responsible for evaluating the experimental design, ensuring scientific rigor, safeguarding participant safety, adhering to medical ethics, and overseeing data management. To protect the privacy rights of each participant, stringent measures will be enforced. Both initial data and outcome indicators will be securely stored in a highly protected database. Additionally, anonymization procedures will be strictly adhered to, ensuring the safety and confidentiality of all participants' information. Confidentiality {27} Personal information related to both potential and enrolled participants will be collected and maintained with the utmost confidentiality throughout all stages of the trial. Informed consent, detailing the study's objectives, procedures, and associated risks, will be obtained from each participant prior to the commencement of the study. Throughout the trial, all data collected will be anonymized and stored securely, with access restricted to authorized personnel responsible for data analysis and trial supervision. Upon the trial's conclusion, all personal information will continue to be protected under stringent safeguarding protocols. Any remaining identifiable data, including specific protocol codes, will be securely archived in compliance with the mandated retention period as prescribed by institutional and regulatory guidelines on confidentiality and data protection. Statistical methods Statistical methods for primary and secondary outcomes {20a} The data analysis will be conducted using the Statistical Package for Social Sciences (SPSS) version 26. To ensure the accuracy of the data entry, it will be performed by two independent researchers who will cross-verify the input data for consistency. The baseline characteristics will be assessed using appropriated statistical tests based on the data distribution: independent t-tests for normally distributed data, Mann-Whitney U tests for non-parametric data, and Chi-square tests for categorical variables. If the parameters meet the criteria for normal distribution, a repeated-measures analysis of variance (RM ANOVA) will be utilized to evaluate the group × time interaction effects and the main effect of time. In cases where significant results are obtained, post-hoc analyses with Bonferroni adjustments will be conducted to control for multiple comparisons. The magnitude of the effects will be quantified using partial eta-squared (η p 2 ), with thresholds of 0.01, 0.06, and 0.14 indicating small, medium, and large effect sizes, respectively. Subsequently, all analyses will be reiterated after the exclusion of drop-outs to conduct a per-protocol analysis. A significance level of 0.05 will be applied throughout the study to determine statistical significance. Interim analyses {21b} An interim analysis will be performed once the trial has enrolled half of the required sample size. This analysis will serve to monitor the emerging trends in outcomes and to verify the integrity of the trial procedures. Methods for additional analyses (e.g. subgroup analyses) {20b} Not applicable. No additional analyses beyond the primary and secondary outcomes will be conducted for the study. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Intention-to-treat analysis (ITT) approach will be used for data analysis. If data are missing, the last observation carried forward method will be adopted. Plans to give access to the full protocol, participant-level data, and statistical code {31c} The study data and statistical code are accessible upon reasonable request from the corresponding author. Additionally, the complete protocol can be obtained from the same correspondence. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The Safety Supervision Committee from the coordinating hospital will oversee the project, bearing the primary responsibility for assessing the experimental design, ensuring scientific rigor, and maintaining procedural integrity throughout the study. This committee is also tasked with safeguarding the well-being of participants, upholding medical ethics, and managing the collection and processing of data with diligence. The Trial Steering Committee will convene to evaluate the recruitment of eligible study participants and will supervise key milestones, including the initiation of the trial. Regular meetings are scheduled at strategic intervals aligned with data collection phases. Both committees offer extensive support for the trial, covering all aspects from pre-trial preparations to post-trial and follow-up assessments, to ensure thorough data collection and robust analysis. Patient Public Involvement and Public Involvement Group The trial is designed to actively involve patients through ongoing dialogue between the coordinating trial team and potential participants within the hospital environment. This approach is crucial for ensuring that patients have a thorough understanding and are able to make informed decisions about their participation. The increased interest from patients in joining the study highlights the importance of transparent communication, which is a cornerstone of the trial's strategy. By enhancing the understanding of the informed consent process, this method not only promotes patient engagement in clinical research but also strengthens transparency and trust within the healthcare community. Composition of the data monitoring committee, its role and reporting structure {21a} To ensure the integrity and quality of the study, a Data Monitoring Committee (DMC) will be established, comprising a diverse group of experts. The DMC will be responsible for periodically reviewing the trial data to monitor patient safety, assess the progress of the study, and provide guidance on the continuation, modification, or termination of the trial based on the data's integrity and emerging results. The committee will operate independently and report its findings to the principal investigator and relevant ethical review boards. For data accuracy, data entry will be conducted by two independent researchers. This dual-entry process allows for cross-verification, ensuring the reliability and consistency of the input data, which is critical for maintaining the study's validity and reducing the potential for errors. Adverse event reporting and harms {22} TENS is recognized as a safe therapeutic modality, with no significant adverse events reported in the literature to date. Our research team is committed to the strictest adherence to the guidelines established by the medical ethics committee, ensuring the utmost safety and ethical protection for all study participants. We have protocols in place to meticulously monitor for any adverse events, such as falls, pain, or dizziness, that may occur during the study period. Should any such events occur, regardless of their relation to the study intervention, our team will diligently document the incident and promptly report it to the ethics committee. Following each adverse event, we will review and adjust the intervention regimen as necessary to mitigate risks and ensure participant well-being. It is important to note that there are no anticipated harms associated with trial participation, and no compensation is provided for participation in this study. Our commitment to participant safety and ethical conduct is unwavering, and we will take all necessary measures to maintain the integrity and safety of the study. Frequency and plans for auditing trial conduct {23} The Project Management Group will hold regular meetings on a monthly basis to rigorously assess the trial’s progress and ensure strict adherence to the protocol. In addition to this, the Trial Steering Group and the Ethics Committee are instrumental in the continuous monitoring and review process. These committees have the crucial responsibility of supervising the conduct of the trial, protecting the well-being of participants, and preserving the integrity of the data throughout the trial’s duration. This systematic approach facilitates proactive oversight and ensures compliance with established ethical and regulatory benchmarks throughout the trial, thereby enhancing the overall quality and reliability of the research. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Effective communication with the funding body will be maintained through a system of structured notifications. The principal investigator (PI) will be responsible for promptly informing the coordinating centers and ensuring the swift distribution of any revised protocol. Upon receipt of the updated protocol, the PI will incorporate a copy into the Investigator Site File for record-keeping purposes. Any deviations from the protocol will be meticulously documented by completing a breach report form, ensuring a thorough and transparent account of any changes or exceptions. The clinical trial registry will be diligently updated to reflect these modifications, ensuring that the registry accurately mirrors the current procedures of the trial. This meticulous approach is essential for upholding transparency and precision in clinical trial management, complying with regulatory standards, and preserving the integrity of the research process. Dissemination plans {31a} Our dissemination strategy is designed to effectively communicate the trial’s findings to both healthcare professionals and the general public. We will employ a multifaceted approach to share pertinent results, leveraging diverse platforms such as: Conference Presentations: Selected conferences will provide a platform to present our research findings to peers and industry experts, fostering discussion and feedback. Peer-Reviewed Journal Publications: We will target high-impact, reputable journals to publish our study, ensuring that our results are scrutinized and contribute to the scientific literature. Medical Forums and Community Outreach: Engaging with medical forums and community events will help us reach a broader audience, including patients and caregivers. By utilizing these channels, we aim to ensure that the trial's key outcomes and insights are accessible to all stakeholders within the healthcare community and the public at large. To maintain transparency and facilitate the accessibility of our research, regular updates and concise summaries of the findings will be made available. This approach aligns with ethical research standards and supports informed decision-making in healthcare practices. Discussion The primary goal of this trial is to investigate the effects of Lo-TENS on individuals with multimorbidity. This study is meticulously designed to test the central hypothesis that Lo-TENS can significantly improve clinical outcomes associated with common chronic disease multimorbidity. The study aims to achieve two key objectives: To rigorously evaluate whether Lo-TENS can effectively regulate metabolic indicators that play a crucial role in the pathophysiology of multimorbidity. To identify any differences in the therapeutic effects of Lo-TENS on various single diseases (hypertension, type 2 diabetes, hyperlipidemia) within the same individual with multimorbidity. The significance of this trial is considerable, as it seeks to provide evidence-based intervention strategies tailored to the unique needs of older adults with multimorbidity. By elucidating the neuroendocrinological mechanisms through which Lo-TENS alleviates clinical indicators of multimorbidity, this study aims to confirm the therapeutic efficacy of Lo-TENS in this context. Gaining this knowledge is essential for advancing personalized treatment plans that are both effective and safe for this vulnerable patient population. In summary, the results of this study are expected to provide clinically relevant data that will inform practice through evidence-based guidelines and enhance the scientific discourse on the application of Lo-TENS for managing multimorbidity. The anticipated findings are poised to offer significant insights into clinical practice and stimulate further research and innovation in related areas. Trial status This trial will start to recruit participants on December 23, 2024, and will complete the recruitment on June 22, 2025. Protocol version 1, July 2, 2024. Abbreviations ABPM: ambulatory blood pressure monitor (the average, standard deviation, maximum and minimum values of patient's daytime, nighttime, and all-day systolic, diastolic blood pressure, mean arterial pressure, and pulse pressure); CRP: C-reactive protein; ECG: electrocardiogram; EH: essential hypertension; FBG: fasting blood glucose; FGF21: fibroblast growth factor 21; HbA1c: glycosylated hemoglobin; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein; LDL-cholesterol: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; TC: total cholesterol; TG: triglyceride; TNF-α: tumor necrosis factor-α. Declarations Acknowledgements The authors thank all members who assisted in the preparation of this manuscript and study. Authors’ contributions {31b} Xiang Li, An Yu, Wei Zhang and Lei Yang are involved in the conception and design of the research. Ethics approval was obtained from Lei Yang. Xiang Li, An Yu, Wei Zhang and Lei Yang drafted the manuscript. Liuyan Wang, Mei Xie, Xi Chen, Xiaoyan Mo, Rui Li, Ying Gao, Bijuan Liang, and Qi Wu offered subject-matter expertise and support throughout all stages of manuscript preparation. All the authors edited and revised the manuscript. All the authors read and approved the final version of the manuscript. Funding {4} This study was supported by the funding for Kunming Health Science and Technology Talent Training Project, Kunming Geriatric Syndrome Rehabilitation Treatment Medical Technology Center [No. 2023-SW (Technology)-26]. Availability of data and materials {29} Lei Yang has access to the final trial datasets. Ethics approval and consent to participate {24} The trial has been granted ethical approval by the Second People's Hospital of Kunming Ethics Committee (approval number: 202401011). Informed consent form to participate will be obtained from all participants. Consent for publication {32} All the authors read the manuscript and approved the publication. Competing interests {28} All the authors have no competing interests. References Skou ST, Mair FS, Fortin M, Guthrie B, Nunes BP, Miranda JJ, et al. Multimorbidity. Nat Rev Dis Primers. 2022;8(1):48. Khunti K, Chudasama YV, Gregg EW, Kamkuemah M, Misra S, Suls J, et al. Diabetes and Multiple Long-term Conditions: A Review of Our Current Global Health Challenge. Diabetes Care. 2023;46(12):2092-101. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, et al. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev. 2011;10(4):430-9. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380(9836):37-43. Koller D, Schön G, Schäfer I, Glaeske G, van den Bussche H, Hansen H. Multimorbidity and long-term care dependency—a five-year follow-up. BMC Geriatr. 2014;14(1):70. Nunes BP, Flores TR, Mielke GI, Thumé E, Facchini LA. Multimorbidity and mortality in older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2016;67:130-8. Tooth L, Hockey R, Byles J, Dobson A. Weighted multimorbidity indexes predicted mortality, health service use, and health-related quality of life in older women. J Clin Epidemiol. 2008;61(2):151-9. Byles JE, D'Este C, Parkinson L, O'Connell R, Treloar C. Single index of multimorbidity did not predict multiple outcomes. J Clin Epidemiol. 2005;58(10):997-1005. Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med. 2002;162(20):2269-76. Vogeli C, Shields AE, Lee TA, Gibson TB, Marder WD, Weiss KB, et al. Multiple chronic conditions: prevalence, health consequences, and implications for quality, care management, and costs. J Gen Intern Med. 2007;22 Suppl 3(Suppl 3):391-5. Boyd C, Smith CD, Masoudi FA, Blaum CS, Dodson JA, Green AR, et al. Decision Making for Older Adults With Multiple Chronic Conditions: Executive Summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults With Multimorbidity. J Am Geriatr Soc. 2019;67(4):665-73. National Institute for Health and Care Excellence. Multimorbidity: clinical assessment and management. 2016. Dumbreck S, Flynn A, Nairn M, Wilson M, Treweek S, Mercer SW, et al. Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines. BMJ. 2015;350:h949. Guthrie B, Payne K, Alderson P, McMurdo ME, Mercer SW. Adapting clinical guidelines to take account of multimorbidity. BMJ. 2012;345:e6341. May C, Montori VM, Mair FS. We need minimally disruptive medicine. BMJ. 2009;339:b2803. Smith SM, Wallace E, Clyne B, Boland F, Fortin M. Interventions for improving outcomes in patients with multimorbidity in primary care and community setting: a systematic review. Syst Rev. 2021;10(1):271. Valensi P. Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications. Cardiovasc Diabetol. 2021;20(1):170. Grassi G, Drager LF. Sympathetic overactivity, hypertension and cardiovascular disease: state of the art. Curr Med Res Opin. 2024;40(sup1):5-13. Zsombok A, Desmoulins LD, Derbenev AV. Sympathetic circuits regulating hepatic glucose metabolism: where we stand. Physiol Rev. 2024;104(1):85-101. Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. J Am Soc Hypertens. 2016;10(5):457-66. Russo B, Menduni M, Borboni P, Picconi F, Frontoni S. Autonomic Nervous System in Obesity and Insulin-Resistance-The Complex Interplay between Leptin and Central Nervous System. Int J Mol Sci. 2021;22(10):5187. Grassi G, Seravalle G, Quarti-Trevano F. The 'neuroadrenergic hypothesis' in hypertension: current evidence. Exp Physiol. 2010;95(5):581-6. Hjemdahl P. Can the metabolic syndrome be explained by a unifying concept? Lancet Diabetes Endocrinol. 2015;3(2):96-8. Stein C, Dal Lago P, Ferreira JB, Casali KR, Plentz RD. Transcutaneous electrical nerve stimulation at different frequencies on heart rate variability in healthy subjects. Auton Neurosci. 2011;165(2):205-8. Mokhtari T, Ren Q, Li N, Wang F, Bi Y, Hu L. Transcutaneous Electrical Nerve Stimulation in Relieving Neuropathic Pain: Basic Mechanisms and Clinical Applications. Curr Pain Headache Rep. 2020;24(4):14. Yu A, Li X, Zhang W, Zhang Y, Chen X, Wang L, et al. Adjunctive benefits of low-frequency transcutaneous electrical nerve stimulation for obesity frequent chronic conditions: a systematic review. Front Endocrinol (Lausanne). 2024;15:1424771. Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ. 2014;348:g1687. Climie RE, Schultz MG, Nikolic SB, Ahuja KD, Fell JW, Sharman JE. Validity and reliability of central blood pressure estimated by upper arm oscillometric cuff pressure. Am J Hypertens. 2012;25(4):414-20. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res. 2014;37(4):253-390. Thomas BL, Claassen N, Becker P, Viljoen M. Validity of Commonly Used Heart Rate Variability Markers of Autonomic Nervous System Function. Neuropsychobiology. 2019;78(1):14-26. Tu JF, Wang LQ, Liu JH, Qi YS, Tian ZX, Wang Y, et al. Home-based transcutaneous electrical acupoint stimulation for hypertension: a randomized controlled pilot trial. Hypertens Res. 2021;44(10):1300-6. Lu JY, Ou HY, Wu CZ, Yang CY, Jiang JY, Lu CH, et al. A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes. Sci Rep. 2023;13(1):2662. Wu ZY, Yang M, Jia J, Wu Y, Huang TS, Li MF, et al. Effect of transcutaneous electrical nerve stimulation at acupoints on patients with type 2 diabetes mellitus: a randomized controlled trial. J Tradit Chin Med. 2015;35(2):134-40. Tables Table 1. The intervention protocol for each group base on the TIDieR template Item Lo-TENS plus routine clinical management group Sham stimulation plus routine clinical management group 1. Why The stimulation protocol is adopted from previous studies. A self-adhesive electrode plate is affixed to the dorsal aspect of the first and second metacarpal bones, an additional electrode plate is positioned over the muscle belly of the proximal radius, with both upper limbs receiving the same placement (Figure 2). Therefore, the same protocol was adopted in our trial. The routine clinical management is to ensure participants’ multimorbidity is stable. The sham stimulation group served as an active control group, enabling us to determine whether the observed changes in the stimulation groups are a function of maturation, repeated testing, or placebo effect. 2. What materials KD-2A, Yaoyang Kangda Electronic Instrument Co., Ltd, Beijing, China. 5 X 5 cm self-adhesive electrodes. KD-2A, Yaoyang Kangda Electronic Instrument Co., Ltd, Beijing, China. 5 X 5 cm self-adhesive electrodes. 3. Procedures Participants will be sitting in a comfortable chair. After cleaning the skin, Lo-TENS therapy will be performed. One channel to one upper limb, and both upper limbs will be placed. The placement of electrodes is the same as in group 1. 4. Who provided Experienced physiotherapists Experienced physiotherapists 5. How The stimulation parameters are set as follows: mode, continuous; waveform, bidirectional asymmetric square wave; pulse width, 200 μs; frequency, 2 Hz. The stimulation intensity in milliamps (mA) will be tailored to the individual’s sensation, permitting slight muscle contraction but ensuring that pain or any discomfort is avoided. Except there will be no actual treatment, the other setting will be the same as in group 1. 6. Where The therapy will be performed in the physiotherapy room of the hospitals. The therapy will be performed in another physiotherapy room of the hospitals. 7. When and how much Participants in this group will undergo their stimulation in one 30-minute session per day, over a period of 5 days per week, for a total of 4 consecutive weeks (resulting in 20 sessions in total). Except there will be no actual treatment, the others will be the same as in group 1. 8. Tailoring The stimulating intensity will be tailored to the participant’s tolerance, but without any pain or discomfort. Since no actual electrical current will be generated, tailoring stimulation intensity is not possible in this group. However, participants can adjust their positions, either in lying, or in sitting positions. 9. How well The assessors will be blinded to the group allocation, in order to ensure the objectivity and impartiality of the assessments. The assessors will be blinded to the group allocation, in order to ensure the objectivity and impartiality of the assessments. Table 2 is available in the Supplementary Files section. Supplementary Files Table2.docx Appendix1.TENSandMultimorbiditySPIRITchecklist.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 07 Sep, 2025 Reviewers agreed at journal 03 May, 2025 Reviewers invited by journal 30 Apr, 2025 Editor invited by journal 15 Feb, 2025 Editor assigned by journal 02 Feb, 2025 First submitted to journal 09 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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03:08:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5800105/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5800105/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82273313,"identity":"e3d4f818-09b1-4df1-b9a4-50cf9f7cc187","added_by":"auto","created_at":"2025-05-08 14:28:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49567,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5800105/v1/78851271fc7b8a248b72497d.png"},{"id":82273319,"identity":"79580dbc-ac96-4bb4-ac92-8416249a26fa","added_by":"auto","created_at":"2025-05-08 14:28:19","extension":"png","order_by":2,"title":"Figure 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14:28:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23261,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5800105/v1/0d04349e699c8316c072001f.docx"},{"id":82274847,"identity":"4dc95105-a3d0-4c10-9498-3691a0243c5c","added_by":"auto","created_at":"2025-05-08 14:36:19","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":40209,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1.TENSandMultimorbiditySPIRITchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5800105/v1/873b84a3542ba59aa4869922.docx"}],"financialInterests":"","formattedTitle":"Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults: study protocol for a randomized controlled trial","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eTitle\u0026nbsp;{1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eEffects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eChinese Clinical Trial Registry reference: www.chictr.org.cn (No. ChiCTR2400093956)\u003c/p\u003e\n \u003cp\u003eTrial Registration Data Set of this trial is not relevant to World health organization\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eFirst version\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eKunming Health Science and Technology Talent Training Project, Kunming Geriatric Syndrome Rehabilitation Treatment Medical Technology Center [No. 2023-SW (Technology)-26].\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eXiang Li\u003csup\u003e1\u003c/sup\u003e, An Yu\u003csup\u003e2\u003c/sup\u003e, Liuyan Wang\u003csup\u003e1\u003c/sup\u003e, Mei Xie\u003csup\u003e1\u003c/sup\u003e, Xi Chen\u003csup\u003e1\u003c/sup\u003e, Rui Li\u003csup\u003e1\u003c/sup\u003e, Ying Gao\u003csup\u003e1\u003c/sup\u003e, Bijuan Liang\u003csup\u003e3\u003c/sup\u003e, Qi Wu\u003csup\u003e3\u003c/sup\u003e, Wei Zhang\u003csup\u003e4*\u003c/sup\u003e, Lei Yang\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Rehabilitation Medicine, The Second People\u0026rsquo;s Hospital of Kunming, Kunming, Yunnan, China\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003eYunnan Key Laboratory for Basic Research On Bone and Joint Diseases, Kunming University, Kunming, Yunnan, China\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Geriatrics, The Second People\u0026rsquo;s Hospital of Kunming, Kunming, Yunnan, China\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Rehabilitation Medicine, Yan An Hospital of Kunming City, Kunming, Yunnan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eThe provision of trial sponsor contact information is not applicable to our research.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.3434%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.6566%;\"\u003e\n \u003cp\u003eThe sponsor played no part in study design,\u0026nbsp;collection, management, analysis, and interpretation of data, writing of the report, or\u0026nbsp;the decision to submit the report for publication.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA primary challenge in the traditional clinical management of the older adults stems from the concurrent presence of multiple chronic conditions, or multimorbidity, which often span across different organ systems and discipline-based boundaries [1,2]. Conditions such as essential hypertension (EH), type 2 diabetes mellitus (T2DM), and hyperlipidemia are common examples [3-5]. Multimorbidity is increasingly becoming the norm rather than the exception among older adults [1,6]. The rate of multimorbidity rises significantly with advancing age [3,4], affecting 55% to 98% of the elderly population [5,6].\u003c/p\u003e\n\u003cp\u003eCompelling evidence indicates that individuals with multimorbidity are at a higher risk of premature mortality [5,6], have an alarming 99-fold increased likelihood of hospitalization for ambulatory care-sensitive conditions, and experience more rapid functional decline and higher disability rates [7,8]. Additionally, they are more prone to reliance on long-term care, tend to report a lower quality of life and incur significantly higher healthcare costs [9,10].\u003c/p\u003e\n\u003cp\u003eAlthough numerous guidelines on the clinical management of multimorbidity have been published [11,12], the effective implementation of these guidelines is often hindered by the overlay of multiple conditions as well as the adverse events and/or the drug interactions associated with polypharmacy [13], leading to an unsatisfactorily low level of multimorbidity management [14,15].\u003c/p\u003e\n\u003cp\u003eSubsequently, escalating research endeavors have been oriented towards uncovering alternative strategies to optimize multimorbidity management outcomes within the older adults [16]. Research has demonstrated that sympathetic over-activation is prevalent among individuals with essential EH, T2DM, and hyperlipidemia, playing a pivotal role in the initiation, perpetuation, and progression of these diseases [17-21]. These findings have given rise to the neurogenic hypothesis of common chronic diseases in the elderly, underscoring the potential pathophysiological significance of sympathetic neural abnormalities [22,23].\u003c/p\u003e\n\u003cp\u003eConsidering the adverse effects of sympathetic over-activation, it is plausible that alleviating sympathoexcitation could provide clinical benefits in managing morbidity in older adults. Stein et al. discovered that in healthy subjects, low-frequency (2 Hz) transcutaneous electrical nerve stimulation (Lo-TENS) can reduce sympathetic nervous system activity and enhance parasympathetic nervous system activity, while high-frequency (100 Hz) TENS increases sympathetic nervous system activity when applied to the paravertebral ganglion regions [24]. Moreover, TENS is recognized for its cost-effectiveness, self-administration feasibility [25], and minimal side effects compared to other treatment modalities, positioning it as a promising alternative or adjunct to current standard therapies in the management of common chronic diseases [26].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, no research has yet assessed the impact of Lo-TENS on the management of multimorbidity in older adults. This randomized controlled trial is thus designed to examine the efficacy of integrating Lo-TENS into the management of multimorbidity (EH, T2DM, and hyperlipidemia) in this demographic. This study hypothesizes that the incorporation of Lo-TENS as an adjunct therapy will enhance multimorbidity management outcomes in the older adults, surpassing the effects of traditional clinical management alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study will employ a prospective, single-blind, parallel-group, randomized controlled clinical trial design. Following the initial baseline assessment, participants will be randomly allocated to one of the two arms: 1) the Lo-TENS plus routine clinical management group; or 2) the sham stimulation plus routine clinical management group. Figure 1 illustrates the trial\u0026rsquo;s flow diagram. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is detailed in Appendix I.\u003c/p\u003e"},{"header":"Methods: Participants, interventions, and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study setting will be in The Second People\u0026rsquo;s Hospital of Kunming.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria for this study are as follows:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eParticipants must be aged between 60 and 80 years;\u003c/li\u003e\n \u003cli\u003eThey must have co-existed two or more of the following chronic conditions: EH, T2DM, and hyperlipidemia, for at least one year;\u003c/li\u003e\n \u003cli\u003eParticipants must be medically stable;\u003c/li\u003e\n \u003cli\u003eThey must be capable of understanding and following 3-step commands;\u003c/li\u003e\n \u003cli\u003eParticipants must have provided signed informed consent.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe exclusion criteria include:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eContraindications to electrical stimulation therapy, such as the presence of a cardiac pacemaker, metal implants, skin conditions affecting the treatment area (e.g., scratches, inflammation), or a history of epilepsy or tumors;\u003c/li\u003e\n \u003cli\u003eUse of medications, other than routine therapy for managing co-existing chronic diseases, that affect blood pressure, blood sugar, and/or lipids within the past two months (e.g., glucocorticoids, central nervous system inhibitors);\u003c/li\u003e\n \u003cli\u003eSevere cognitive or speech impairments that would interfere with study participation;\u003c/li\u003e\n \u003cli\u003eOther serious illnesses that could influence blood pressure, blood sugar, and/or lipids;\u003c/li\u003e\n \u003cli\u003eParticipation in another clinical trial within the past two months.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProfessional rehabilitation therapists will provide a comprehensive explanation of the trial to potential participants. Should participants express a willingness to participate, the therapist will then proceed to obtain their signature on the informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No additional consent provisions are required for the collection and utilization of participant data and biological specimens within the scope of this trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood pressure, blood sugar, and lipid levels are susceptible to influences from various factors, including medication, exercise, and mobility, among others. Consequently, a sham stimulation is employed in this study to discern whether observed changes in these health indicators are due to external factors or the actual treatment stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe stimulation protocol for both groups was meticulously designed in accordance with the research intervention description of the TIDieR (Template for Intervention Description and Replication) template [27], with specific details outlined in Table 1. Participants in each group will undergo their assigned stimulation in one 30-minute session per day, over a period of 5 days per week, for a total of 4 consecutive weeks (resulting in 20 sessions in total). To ensure the blinding process, the stimulation sessions for the two groups will be held in separate physical agent therapy rooms, preventing participants from discussing their experiences with the stimulation. Throughout the stimulation period, participants will be closely monitored and supervised to ensure their safety and to minimize the risk of emergencies or adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLo-TENS\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be seated in a comfortable chair. Prior to the application of low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) therapy using the KD-2A device from Yaoyang Kangda Electronic Instrument Co., Ltd in Beijing, China, the skin will be thoroughly cleaned. A self-adhesive electrode plate measuring 5 x 5 cm will be affixed to the dorsal aspect of the first and second metacarpal bones. An additional electrode plate will be positioned over the muscle belly of the proximal radius, with both upper limbs receiving the placement (refer to Figure 2). The stimulation parameters are set as follows: mode, continuous; waveform, bidirectional asymmetric square wave; pulse width, 200 \u0026mu;s; frequency, 2 Hz. The stimulation intensity in milliamps (mA) will be tailored to the individual\u0026rsquo;s sensation, permitting slight muscle contraction but ensuring that pain or any discomfort is avoided.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSham Stimulation\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in the control group will receive the sham stimulation, i.e., only the electrodes are placed, and the stimulation parameters are the same, but no actual treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRoutine clinical management\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in both groups will take their regular medications to control their multimorbidity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) is inherently safe, should participants experience any irreversible stimulation-related adverse events such as nausea, dizziness, disorientation, postural instability, or fatigue during the trial, their participation will be discontinued immediately to ensure their well-being and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following measures will be taken to achieve the best intervention adherence:\u003c/p\u003e\n\u003cp\u003e1. The intervention schedule of the participant can be adjusted according to the actual availability of time of the day.\u003c/p\u003e\n\u003cp\u003e2. Close attention is always given to the feedback of participants during stimulation.\u003c/p\u003e\n\u003cp\u003e3. Participants\u0026rsquo; medications, exercise, and mobility levels will be assessed weekly; and\u003c/p\u003e\n\u003cp\u003e4. Participants\u0026rsquo; decision to withdraw from the trial will be supported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No limitations are imposed on concurrent care throughout the duration of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Ancillary and post-trial care provisions are considered unnecessary for the current study design. Additionally, no compensation for trial participation is planned, as the trial is not expected to cause any harm to participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComprehensive demographic information, including age, gender, type of diseases, onset time, and medication details, will be gathered during the initial baseline assessment. Outcome measurements will be conducted by an assessor who is unaware of the treatment allocation on three separate occasions: initially at baseline, following the intervention\u0026rsquo;s completion, and at the 4-week follow-up point (as detailed in Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrimary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOffice blood pressure:\u0026nbsp;\u003c/em\u003eSystolic blood pressure (SBP) and diastolic blood pressure (DBP) will be measured using an electronic sphygmomanometer (HEM-7136, Omron Corporation, Kyoto, Japan). Participants will be instructed to remain at rest for a minimum of 5 minutes. Subsequently, SBP and DBP will be measured on both arms, while the participant is seated and the measuring arm is positioned at heart level [28]. The arm with the higher SBP will be designated as the research arm. The blood pressure will be measured three times at 5-minute intervals, and the average of the three readings will be recorded [29]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFasting blood glucose (FBG):\u003c/em\u003e After waking up in the morning and fasting for more than 8 hours without consuming any food, medication, or insulin, check the blood sugar levels.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLow-Density Lipoprotein Cholesterol (LDL-C):\u0026nbsp;\u003c/em\u003eOften referred to as \u0026quot;bad\u0026quot; cholesterol because high levels can lead to plaque buildup in the arteries, increasing the risk of heart disease and stroke. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTriglycerides:\u0026nbsp;\u003c/em\u003eTriglycerides are a type of blood fat that serves as the primary source of energy for the body. Elevated triglyceride levels are associated with an increased risk of heart and vascular disease, including heart attack and stroke. Very high triglyceride levels can cause acute inflammation of the pancreas, known as pancreatitis. This condition can be severe, painful, and potentially life-threatening.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSympathetic nerve activity\u003c/em\u003e: A 24-hour ambulatory electrocardiogram (ECG) system (model ER1, Shenzhen Yuandong Innovation Technology Co., Ltd., Shenzhen, China) will be utilized to capture the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz) components of participants\u0026rsquo; heart rate and heart rate variability (HRV). From these recordings, the sympathetic-vagal index (LF/HF ratio) will be derived to assess sympathetic nerve activity. The LF/HF ratio will be categorized as low, moderate, or high, with threshold values set at 0.2, 0.5, and 0.8, respectively [30]. Participants are instructed to carry out their regular daily activities throughout the 24-hour ECG monitoring period. All collected data will be digitally stored on a computer and subsequently analyzed by a trained analyst.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e24-hour blood pressure:\u0026nbsp;\u003c/em\u003eA 24-hour ambulatory blood pressure monitor (ABPM) (SY-B-003, Hunan Saihong Medical Technology Co., Ltd., Changsha, China) will be used to collect data on the mean, standard deviation, maximum and minimum values of patient\u0026rsquo;s all-day systolic, diastolic blood pressure, mean arterial pressure, and pulse pressure.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBlood test:\u0026nbsp;\u003c/em\u003ePeripheral blood of the participants will be extracted by the experienced nurses, and the concentrations of plasma\u0026nbsp;glucose, glycosylated hemoglobin (HbA1c), insulin, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) will be measured by the laboratory department in the hospital.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBiochemical indicators:\u0026nbsp;\u003c/em\u003eThe peripheral blood will also be used to assess the following indicators: C-reactive protein (CRP), adiponectin, tumor necrosis factor-\u0026alpha; (TNF-\u0026alpha;)，fibroblast growth factor 21 (FGF21), and\u0026nbsp;norepinephrine, IL-6, IL-1\u0026beta;, IL-11.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTimeline for participants\u0026rsquo; enrolment, interventions, and assessments is shown in Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample size estimation for our study was conducted using G*Power 3.1 software (Heinrich-Heine-Universitat, Dusseldorf, Germany). Given the three primary outcome measures in our study\u0026mdash;blood pressure, glycemia, and lipid levels\u0026mdash;it was essential to approach sample size estimation comprehensively.\u003c/p\u003e\n\u003cp\u003eFor blood pressure, a study by Tu et al. reported that after a 12-week intervention, Lo-TENS led to a significantly greater reduction in systolic blood pressure (SBP) compared to maintaining medication and health education, with a Cohen\u0026apos;s d effect size of 0.93 (equivalent to f=0.465) [31].\u003c/p\u003e\n\u003cp\u003eIn the case of glycemia, a study by Lu et al. investigated the effects of Lo-TENS on individuals with T2DM. They found that after a 20-week intervention, the Lo-TENS group experienced a significantly greater reduction in fasting plasma glucose (FPG) compared to the placebo group, with a Cohen\u0026apos;s d effect size of 0.565 (equivalent to f=0.282) [32].\u003c/p\u003e\n\u003cp\u003eFor lipid levels, Wu et al. demonstrated significant reductions in total cholesterol (TC) and triglycerides (TG) after an 8-week intervention, with Cohen\u0026apos;s d effect sizes of 1.286 and 1.327 (equivalent to f=0.643 and 0.663), respectively [33].\u003c/p\u003e\n\u003cp\u003eConsidering these findings, we adopted the smallest effect size (f=0.282) from the Lu et al. study for our sample size calculations. Additionally, our trial features a shorter intervention period of 4 weeks and does not include lifestyle modifications, exercise programs, or diet management as part of the intervention. Based on a 2 \u0026times; 3 analysis of variance (ANOVA), assuming a medium effect size (f=0.2), an alpha level of 0.05, a power of 0.80, and an attrition rate of 20%, the estimated sample size required is 50 participants in total, with 25 participants per group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRecruitment {15}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in the study will be enrolled in The Second People\u0026apos;s Hospital of Kunming. The research team will initially conduct a screening process to determine the eligibility of potential participants. Throughout the follow-up period, patients will be kept informed about the research\u0026rsquo;s progress and will be provided with updates on their individual results. Additionally, researchers will maintain ongoing communication with the physicians overseeing the care of each participant. Upon the study\u0026apos;s conclusion, both the medical professionals and patients will receive a comprehensive final report detailing the outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAssignment of interventions: allocation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSequence generation {16a}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study investigator will use the online tool (www.randomization.com) to generate the randomization sequence. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConcealment mechanism {16b}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment allocation will be concealed in an opaque envelope from the study investigator and kept closed until the baseline assessment is completed by a blinded assessor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eImplementation {16c}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principal investigator will assign participants to one of the two groups according to the randomization sequence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAssignment of interventions: Blinding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eWho will be blinded {17a}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be blinded to the stimulation condition (real stimulation or sham stimulation), and told that \u0026ldquo;the skin sensation induced by electrical stimulation is very little\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Emergency unblinding to our trial is not applicable because it is impossible to blind the therapist in our trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure the quality and integrity of the research prior to the trial\u0026apos;s commencement, we will conduct comprehensive training for all involved personnel and verify the functionality of all relevant equipment. The steps we will take include:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eEnsuring that the recruiting physicians have a thorough understanding of the experimental procedures;\u003c/li\u003e\n \u003cli\u003eTraining physical therapists in the precise execution of the intervention program, as well as in the management of any potential adverse events that may occur during stimulation;\u003c/li\u003e\n \u003cli\u003eProviding assessors with training on the proper collection and processing of outcome measures.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA follow-up assessment will be scheduled four weeks post-intervention. Participants will be contacted via telephone and invited to return to the hospital for this assessment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Safety Supervision Committee from the participating hospitals will have overall oversight of this project. They will be responsible for evaluating the experimental design, ensuring scientific rigor, safeguarding participant safety, adhering to medical ethics, and overseeing data management. To protect the privacy rights of each participant, stringent measures will be enforced. Both initial data and outcome indicators will be securely stored in a highly protected database. Additionally, anonymization procedures will be strictly adhered to, ensuring the safety and confidentiality of all participants\u0026apos; information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePersonal information related to both potential and enrolled participants will be collected and maintained with the utmost confidentiality throughout all stages of the trial. Informed consent, detailing the study\u0026apos;s objectives, procedures, and associated risks, will be obtained from each participant prior to the commencement of the study. Throughout the trial, all data collected will be anonymized and stored securely, with access restricted to authorized personnel responsible for data analysis and trial supervision. Upon the trial\u0026apos;s conclusion, all personal information will continue to be protected under stringent safeguarding protocols. Any remaining identifiable data, including specific protocol codes, will be securely archived in compliance with the mandated retention period as prescribed by institutional and regulatory guidelines on confidentiality and data protection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data analysis will be conducted using the Statistical Package for Social Sciences (SPSS) version 26. To ensure the accuracy of the data entry, it will be performed by two independent researchers who will cross-verify the input data for consistency. The baseline characteristics will be assessed using appropriated statistical tests based on the data distribution: independent t-tests for normally distributed data, Mann-Whitney U tests for non-parametric data, and Chi-square tests for categorical variables.\u003c/p\u003e\n\u003cp\u003eIf the parameters meet the criteria for normal distribution, a repeated-measures analysis of variance (RM ANOVA) will be utilized to evaluate the group \u0026times; time interaction effects and the main effect of time. In cases where significant results are obtained, post-hoc analyses with Bonferroni adjustments will be conducted to control for multiple comparisons. The magnitude of the effects will be quantified using partial eta-squared (\u0026eta;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e), with thresholds of 0.01, 0.06, and 0.14 indicating small, medium, and large effect sizes, respectively.\u003c/p\u003e\n\u003cp\u003eSubsequently, all analyses will be reiterated after the exclusion of drop-outs to conduct a per-protocol analysis. A significance level of 0.05 will be applied throughout the study to determine statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInterim analyses {21b}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn interim analysis will be performed once the trial has enrolled half of the required sample size. This analysis will serve to monitor the emerging trends in outcomes and to verify the integrity of the trial procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No additional analyses beyond the primary and secondary outcomes will be conducted for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntention-to-treat analysis (ITT) approach will be used for data analysis. If data are missing, the last observation carried forward method will be adopted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant-level data, and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study data and statistical code are accessible upon reasonable request from the corresponding author. Additionally, the complete protocol can be obtained from the same correspondence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Safety Supervision Committee from the coordinating hospital will oversee the project, bearing the primary responsibility for assessing the experimental design, ensuring scientific rigor, and maintaining procedural integrity throughout the study. This committee is also tasked with safeguarding the well-being of participants, upholding medical ethics, and managing the collection and processing of data with diligence. The Trial Steering Committee will convene to evaluate the recruitment of eligible study participants and will supervise key milestones, including the initiation of the trial. Regular meetings are scheduled at strategic intervals aligned with data collection phases. Both committees offer extensive support for the trial, covering all aspects from pre-trial preparations to post-trial and follow-up assessments, to ensure thorough data collection and robust analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Public Involvement and Public Involvement Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is designed to actively involve patients through ongoing dialogue between the coordinating trial team and potential participants within the hospital environment. This approach is crucial for ensuring that patients have a thorough understanding and are able to make informed decisions about their participation. The increased interest from patients in joining the study highlights the importance of transparent communication, which is a cornerstone of the trial\u0026apos;s strategy. By enhancing the understanding of the informed consent process, this method not only promotes patient engagement in clinical research but also strengthens transparency and trust within the healthcare community.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure the integrity and quality of the study, a Data Monitoring Committee (DMC) will be established, comprising a diverse group of experts. The DMC will be responsible for periodically reviewing the trial data to monitor patient safety, assess the progress of the study, and provide guidance on the continuation, modification, or termination of the trial based on the data\u0026apos;s integrity and emerging results. The committee will operate independently and report its findings to the principal investigator and relevant ethical review boards.\u003c/p\u003e\n\u003cp\u003eFor data accuracy, data entry will be conducted by two independent researchers. This dual-entry process allows for cross-verification, ensuring the reliability and consistency of the input data, which is critical for maintaining the study\u0026apos;s validity and reducing the potential for errors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTENS is recognized as a safe therapeutic modality, with no significant adverse events reported in the literature to date. Our research team is committed to the strictest adherence to the guidelines established by the medical ethics committee, ensuring the utmost safety and ethical protection for all study participants. We have protocols in place to meticulously monitor for any adverse events, such as falls, pain, or dizziness, that may occur during the study period. Should any such events occur, regardless of their relation to the study intervention, our team will diligently document the incident and promptly report it to the ethics committee.\u003c/p\u003e\n\u003cp\u003eFollowing each adverse event, we will review and adjust the intervention regimen as necessary to mitigate risks and ensure participant well-being. It is important to note that there are no anticipated harms associated with trial participation, and no compensation is provided for participation in this study. Our commitment to participant safety and ethical conduct is unwavering, and we will take all necessary measures to maintain the integrity and safety of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Project Management Group will hold regular meetings on a monthly basis to rigorously assess the trial\u0026rsquo;s progress and ensure strict adherence to the protocol. In addition to this, the Trial Steering Group and the Ethics Committee are instrumental in the continuous monitoring and review process. These committees have the crucial responsibility of supervising the conduct of the trial, protecting the well-being of participants, and preserving the integrity of the data throughout the trial\u0026rsquo;s duration. This systematic approach facilitates proactive oversight and ensures compliance with established ethical and regulatory benchmarks throughout the trial, thereby enhancing the overall quality and reliability of the research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEffective communication with the funding body will be maintained through a system of structured notifications. The principal investigator (PI) will be responsible for promptly informing the coordinating centers and ensuring the swift distribution of any revised protocol. Upon receipt of the updated protocol, the PI will incorporate a copy into the Investigator Site File for record-keeping purposes.\u003c/p\u003e\n\u003cp\u003eAny deviations from the protocol will be meticulously documented by completing a breach report form, ensuring a thorough and transparent account of any changes or exceptions. The clinical trial registry will be diligently updated to reflect these modifications, ensuring that the registry accurately mirrors the current procedures of the trial. This meticulous approach is essential for upholding transparency and precision in clinical trial management, complying with regulatory standards, and preserving the integrity of the research process.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur dissemination strategy is designed to effectively communicate the trial\u0026rsquo;s findings to both healthcare professionals and the general public. We will employ a multifaceted approach to share pertinent results, leveraging diverse platforms such as:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eConference Presentations: Selected conferences will provide a platform to present our research findings to peers and industry experts, fostering discussion and feedback.\u003c/li\u003e\n \u003cli\u003ePeer-Reviewed Journal Publications: We will target high-impact, reputable journals to publish our study, ensuring that our results are scrutinized and contribute to the scientific literature.\u003c/li\u003e\n \u003cli\u003eMedical Forums and Community Outreach: Engaging with medical forums and community events will help us reach a broader audience, including patients and caregivers.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eBy utilizing these channels, we aim to ensure that the trial\u0026apos;s key outcomes and insights are accessible to all stakeholders within the healthcare community and the public at large. To maintain transparency and facilitate the accessibility of our research, regular updates and concise summaries of the findings will be made available. This approach aligns with ethical research standards and supports informed decision-making in healthcare practices.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary goal of this trial is to investigate the effects of Lo-TENS on individuals with multimorbidity. This study is meticulously designed to test the central hypothesis that Lo-TENS can significantly improve clinical outcomes associated with common chronic disease multimorbidity.\u003c/p\u003e\n\u003cp\u003eThe study aims to achieve two key objectives:\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eTo rigorously evaluate whether Lo-TENS can effectively regulate metabolic indicators that play a crucial role in the pathophysiology of multimorbidity.\u003c/li\u003e\n \u003cli\u003eTo identify any differences in the therapeutic effects of Lo-TENS on various single diseases (hypertension, type 2 diabetes, hyperlipidemia) within the same individual with multimorbidity.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe significance of this trial is considerable, as it seeks to provide evidence-based intervention strategies tailored to the unique needs of older adults with multimorbidity. By elucidating the neuroendocrinological mechanisms through which Lo-TENS alleviates clinical indicators of multimorbidity, this study aims to confirm the therapeutic efficacy of Lo-TENS in this context. Gaining this knowledge is essential for advancing personalized treatment plans that are both effective and safe for this vulnerable patient population.\u003c/p\u003e\n\u003cp\u003eIn summary, the results of this study are expected to provide clinically relevant data that will inform practice through evidence-based guidelines and enhance the scientific discourse on the application of Lo-TENS for managing multimorbidity. The anticipated findings are poised to offer significant insights into clinical practice and stimulate further research and innovation in related areas. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial will start to recruit participants on December 23, 2024, and will complete the recruitment on June 22, 2025. Protocol version 1, July 2, 2024.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eABPM: ambulatory blood pressure monitor (the average, standard deviation, maximum and minimum values of patient\u0026apos;s daytime, nighttime, and all-day systolic, diastolic blood pressure, mean arterial pressure, and pulse pressure); CRP: C-reactive protein; ECG: electrocardiogram; EH: essential hypertension; FBG: fasting blood glucose; FGF21: fibroblast growth factor 21; HbA1c: glycosylated hemoglobin; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein; LDL-cholesterol: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; TC: total cholesterol; TG: triglyceride; TNF-\u0026alpha;: tumor necrosis factor-\u0026alpha;.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all members who assisted in the preparation of this manuscript and study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiang Li, An Yu, Wei Zhang and Lei Yang are involved in the conception and design of the research. Ethics approval was obtained from Lei Yang. Xiang Li, An Yu, Wei Zhang and\u0026nbsp;Lei Yang drafted the manuscript. Liuyan Wang, Mei Xie, Xi Chen, Xiaoyan Mo, Rui Li, Ying Gao, Bijuan Liang,\u0026nbsp;and Qi Wu offered subject-matter expertise and support throughout all stages of manuscript preparation. All the authors edited and revised the manuscript. All the authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the funding for Kunming Health Science and Technology Talent Training Project, Kunming Geriatric Syndrome Rehabilitation Treatment Medical Technology Center [No. 2023-SW (Technology)-26]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLei Yang has access to the final trial datasets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial has been granted ethical approval by the Second People\u0026apos;s Hospital of Kunming Ethics Committee (approval number: 202401011). Informed consent form to participate will be obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors read the manuscript and approved the publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSkou ST, Mair FS, Fortin M, Guthrie B, Nunes BP, Miranda JJ, et al. Multimorbidity. Nat Rev Dis Primers. 2022;8(1):48.\u003c/li\u003e\n\u003cli\u003eKhunti K, Chudasama YV, Gregg EW, Kamkuemah M, Misra S, Suls J, et al. Diabetes and Multiple Long-term Conditions: A Review of Our Current Global Health Challenge. Diabetes Care. 2023;46(12):2092-101.\u003c/li\u003e\n\u003cli\u003eMarengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, et al. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev. 2011;10(4):430-9. \u003c/li\u003e\n\u003cli\u003eBarnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380(9836):37-43.\u003c/li\u003e\n\u003cli\u003eKoller D, Sch\u0026ouml;n G, Sch\u0026auml;fer I, Glaeske G, van den Bussche H, Hansen H. Multimorbidity and long-term care dependency\u0026mdash;a five-year follow-up. BMC Geriatr. 2014;14(1):70.\u003c/li\u003e\n\u003cli\u003eNunes BP, Flores TR, Mielke GI, Thum\u0026eacute; E, Facchini LA. Multimorbidity and mortality in older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2016;67:130-8. \u003c/li\u003e\n\u003cli\u003eTooth L, Hockey R, Byles J, Dobson A. Weighted multimorbidity indexes predicted mortality, health service use, and health-related quality of life in older women. J Clin Epidemiol. 2008;61(2):151-9.\u003c/li\u003e\n\u003cli\u003eByles JE, D\u0026apos;Este C, Parkinson L, O\u0026apos;Connell R, Treloar C. Single index of multimorbidity did not predict multiple outcomes. J Clin Epidemiol. 2005;58(10):997-1005. \u003c/li\u003e\n\u003cli\u003eWolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med. 2002;162(20):2269-76.\u003c/li\u003e\n\u003cli\u003eVogeli C, Shields AE, Lee TA, Gibson TB, Marder WD, Weiss KB, et al. Multiple chronic conditions: prevalence, health consequences, and implications for quality, care management, and costs. J Gen Intern Med. 2007;22 Suppl 3(Suppl 3):391-5.\u003c/li\u003e\n\u003cli\u003eBoyd C, Smith CD, Masoudi FA, Blaum CS, Dodson JA, Green AR, et al. Decision Making for Older Adults With Multiple Chronic Conditions: Executive Summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults With Multimorbidity. J Am Geriatr Soc. 2019;67(4):665-73.\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence. Multimorbidity: clinical assessment and management. 2016. \u0026lt;https://www.nice.org.uk/guidance/ng56\u0026gt;\u003c/li\u003e\n\u003cli\u003eDumbreck S, Flynn A, Nairn M, Wilson M, Treweek S, Mercer SW, et al. Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines. BMJ. 2015;350:h949.\u003c/li\u003e\n\u003cli\u003eGuthrie B, Payne K, Alderson P, McMurdo ME, Mercer SW. Adapting clinical guidelines to take account of multimorbidity. BMJ. 2012;345:e6341.\u003c/li\u003e\n\u003cli\u003eMay C, Montori VM, Mair FS. We need minimally disruptive medicine. BMJ. 2009;339:b2803. \u003c/li\u003e\n\u003cli\u003eSmith SM, Wallace E, Clyne B, Boland F, Fortin M. Interventions for improving outcomes in patients with multimorbidity in primary care and community setting: a systematic review. Syst Rev. 2021;10(1):271.\u003c/li\u003e\n\u003cli\u003eValensi P. Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications. Cardiovasc Diabetol. 2021;20(1):170.\u003c/li\u003e\n\u003cli\u003eGrassi G, Drager LF. Sympathetic overactivity, hypertension and cardiovascular disease: state of the art. Curr Med Res Opin. 2024;40(sup1):5-13. \u003c/li\u003e\n\u003cli\u003eZsombok A, Desmoulins LD, Derbenev AV. Sympathetic circuits regulating hepatic glucose metabolism: where we stand. Physiol Rev. 2024;104(1):85-101.\u003c/li\u003e\n\u003cli\u003eGrassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. J Am Soc Hypertens. 2016;10(5):457-66.\u003c/li\u003e\n\u003cli\u003eRusso B, Menduni M, Borboni P, Picconi F, Frontoni S. Autonomic Nervous System in Obesity and Insulin-Resistance-The Complex Interplay between Leptin and Central Nervous System. Int J Mol Sci. 2021;22(10):5187. \u003c/li\u003e\n\u003cli\u003eGrassi G, Seravalle G, Quarti-Trevano F. The \u0026apos;neuroadrenergic hypothesis\u0026apos; in hypertension: current evidence. Exp Physiol. 2010;95(5):581-6.\u003c/li\u003e\n\u003cli\u003eHjemdahl P. Can the metabolic syndrome be explained by a unifying concept? Lancet Diabetes Endocrinol. 2015;3(2):96-8.\u003c/li\u003e\n\u003cli\u003eStein C, Dal Lago P, Ferreira JB, Casali KR, Plentz RD. Transcutaneous electrical nerve stimulation at different frequencies on heart rate variability in healthy subjects. Auton Neurosci. 2011;165(2):205-8. \u003c/li\u003e\n\u003cli\u003eMokhtari T, Ren Q, Li N, Wang F, Bi Y, Hu L. Transcutaneous Electrical Nerve Stimulation in Relieving Neuropathic Pain: Basic Mechanisms and Clinical Applications. Curr Pain Headache Rep. 2020;24(4):14.\u003c/li\u003e\n\u003cli\u003eYu A, Li X, Zhang W, Zhang Y, Chen X, Wang L, et al. Adjunctive benefits of low-frequency transcutaneous electrical nerve stimulation for obesity frequent chronic conditions: a systematic review. Front Endocrinol (Lausanne). 2024;15:1424771. \u003c/li\u003e\n\u003cli\u003eHoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ. 2014;348:g1687.\u003c/li\u003e\n\u003cli\u003eClimie RE, Schultz MG, Nikolic SB, Ahuja KD, Fell JW, Sharman JE. Validity and reliability of central blood pressure estimated by upper arm oscillometric cuff pressure. Am J Hypertens. 2012;25(4):414-20. \u003c/li\u003e\n\u003cli\u003eShimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res. 2014;37(4):253-390. \u003c/li\u003e\n\u003cli\u003eThomas BL, Claassen N, Becker P, Viljoen M. Validity of Commonly Used Heart Rate Variability Markers of Autonomic Nervous System Function. Neuropsychobiology. 2019;78(1):14-26.\u003c/li\u003e\n\u003cli\u003eTu JF, Wang LQ, Liu JH, Qi YS, Tian ZX, Wang Y, et al. Home-based transcutaneous electrical acupoint stimulation for hypertension: a randomized controlled pilot trial. Hypertens Res. 2021;44(10):1300-6.\u003c/li\u003e\n\u003cli\u003eLu JY, Ou HY, Wu CZ, Yang CY, Jiang JY, Lu CH, et al. A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes. Sci Rep. 2023;13(1):2662.\u003c/li\u003e\n\u003cli\u003eWu ZY, Yang M, Jia J, Wu Y, Huang TS, Li MF, et al. Effect of transcutaneous electrical nerve stimulation at acupoints on patients with type 2 diabetes mellitus: a randomized controlled trial. J Tradit Chin Med. 2015;35(2):134-40. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. The\u0026nbsp;intervention protocol for each group base on the TIDieR template\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eItem\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003col\u003e\n \u003cli\u003e\u003cstrong\u003eLo-TENS plus routine clinical management group\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003col start=\"2\"\u003e\n \u003cli\u003e\u003cstrong\u003eSham stimulation plus routine clinical management group\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1. Why\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eThe stimulation protocol is adopted from previous studies. A self-adhesive electrode plate is affixed to the dorsal aspect of the first and second metacarpal bones, an additional electrode plate is positioned over the muscle belly of the proximal radius, with both upper limbs receiving the same placement (Figure 2). Therefore, the same protocol was adopted in our trial.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThe routine clinical management is to ensure participants\u0026rsquo; multimorbidity is stable.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003e\u0026nbsp;The sham stimulation group served as an active control group, enabling us to determine whether the observed changes in the stimulation groups are a function of maturation, repeated testing, or placebo effect.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2. What\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ematerials\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eKD-2A, Yaoyang Kangda Electronic Instrument Co., Ltd, Beijing, China.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 X 5 cm self-adhesive electrodes.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eKD-2A, Yaoyang Kangda Electronic Instrument Co., Ltd, Beijing, China.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 X 5 cm self-adhesive electrodes.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3. Procedures\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eParticipants will be sitting in a comfortable chair. After cleaning the skin, Lo-TENS therapy will be performed. One channel to one upper limb, and both upper limbs will be placed.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eThe placement of electrodes is the same as in group 1.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4. Who provided\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eExperienced physiotherapists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eExperienced physiotherapists\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5. How\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eThe stimulation parameters are set as follows: mode, continuous; waveform, bidirectional asymmetric square wave; pulse width, 200 \u0026mu;s; frequency, 2 Hz. The stimulation intensity in milliamps (mA) will be tailored to the individual\u0026rsquo;s sensation, permitting slight muscle contraction but ensuring that pain or any discomfort is avoided. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eExcept there will be no actual treatment, the other setting will be the same as in group 1.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6. Where\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eThe therapy \u0026nbsp;will be performed in the physiotherapy room of \u0026nbsp;the hospitals.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eThe therapy will be performed in another physiotherapy room of \u0026nbsp;the hospitals.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7. When and\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ehow much\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eParticipants in this group will undergo their stimulation in one 30-minute session per day, over a period of 5 days per week, for a total of 4 consecutive weeks (resulting in 20 sessions in total).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eExcept there will be no actual treatment, the others will be the same as in group 1.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8. Tailoring\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eThe stimulating intensity will be tailored to the participant\u0026rsquo;s tolerance, but without any pain or discomfort.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eSince no actual electrical current will be generated, tailoring stimulation intensity is not possible in this group. However, participants can adjust their positions, either in lying, or in sitting positions.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9. How well\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41.8367%;\"\u003e\n \u003cp\u003eThe assessors will be blinded to the group allocation, in order to ensure the objectivity and impartiality of the assessments.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39.7959%;\"\u003e\n \u003cp\u003eThe assessors will be blinded to the group allocation, in order to ensure the objectivity and impartiality of the assessments.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"multimorbidity, essential hypertension, type 2 diabetes mellitus, hyperlipidemia, transcutaneous electrical nerve stimulation, study protocol, randomized controlled trial ","lastPublishedDoi":"10.21203/rs.3.rs-5800105/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5800105/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u0026nbsp;\u003c/strong\u003eMultimorbidity (≥2 co-existing conditions in an individual), especially co-existing essential hypertension (EH), type 2 diabetes mellitus (T2DM), and hyperlipidemia two or above, is a major global health challenge with substantial impact on individuals, carers and society.\u0026nbsp;This trial aims to examine the efficacy of integrating low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) into the management of multimorbidity (co-existing\u0026nbsp;EH, T2DM, and hyperlipidemia two or above) in older adults and explore the underlying mechanisms through which Lo-TENS may alleviate the clinical indicators of multimorbidity, providing insights into its potential value as a novel adjunctive treatment modality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u0026nbsp;\u003c/strong\u003eThis prospective, randomized controlled trial (RCT) will enroll 50 older adults with multimorbidity, and randomly assign them to one of the two groups: 1) Lo-TENS plus routine clinical management group; or 2) sham stimulation plus routine clinical management group. Participants in each group will receive their respective stimulation one 30 min session/day, 5 days/week, for 4 consecutive weeks. The primary outcomes of interest are blood pressure, blood sugar and blood lipid, with secondary outcomes encompassing heart rate variability and various biochemical indicators. Comprehensive assessments will be performed at baseline, immediately post-intervention, and at 4-week follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u0026nbsp;\u003c/strong\u003eThis trial will provide evidence on the effectiveness of Lo-TENS on clinical outcomes in multimorbidity in older adults, and decipher the working mechanisms of Lo-TENS to multimorbidity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u0026nbsp;\u003c/strong\u003eChinese Clinical Trial Registry Platform: www.chictr.org.cn (No. ChiCTR2400093956).\u003c/p\u003e","manuscriptTitle":"Effects and mechanisms of low-frequency transcutaneous electrical nerve stimulation in relieving common multimorbidity in older adults: study protocol for a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 14:28:14","doi":"10.21203/rs.3.rs-5800105/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-09-08T01:38:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-03T20:28:45+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-30T07:45:35+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-02-15T16:38:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-03T04:33:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-01-09T22:08:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7e97e40c-27d8-4546-bcc6-1f9f2d6a8ef9","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T10:46:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-08 14:28:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5800105","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5800105","identity":"rs-5800105","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}