Hrev_master Comparative efficacy of inter- ferential therapy, bronchodila- tors, and body positioning on asthma control and quality of life of patients with bronchial asthma: A study protocol Eniola Awolola Oladejo, Sonill Maharaj Sooknunan Department of Physiotherapy, College of Health Sciences, University of KwaZulu- Natal, Durban, South Africa Abstract Interferential Therapy (IFT) is the application of two medium frequency cur- rents to the skin to stimulate and activate different systems in the body using specific frequencies and frequency ranges. The aim in applying IFT is to reduce myalgia in the chest and upper back, reduce muscular fatigue, and induce mucus expectoration. This study is designed to test the efficacy of IFT in reducing the symptoms frequently experienced by patients with bronchial asth- ma. Forty-eight (48) patients aged 18 and above with bronchial asthma attending the respiratory clinic at the Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for eligibility. The study design will be a double-blinded, randomized control trial with four interven- tion groups and four parallel placebo con- trol groups. IFT will be administered as an intervention to patients on short and long- acting bronchodilators in an assigned fun- damental body position for 20 minutes. Six continuous outcome variables at different points will be utilized as outcome measures. A baseline Pulmonary Function Test (PFT) will be conducted on entry into the study while quality of life and asthma control will be evaluated every two (2) weeks during the study. Data obtained will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05. The study out- come will compare the efficacy of IFT on bronchial asthma, identify its effect in dif- ferent body positions, and compare the rela- tionship between its application and the bronchodilator medication frequently used by the patients. Introduction Worldwide, approximately 300 million people are affected with bronchial asthma.1 It is more prevalent in developed countries, with the highest rates seen in Australia, UK, and New Zealand.1 In the Nigerian popula- tion, the prevalence of asthma ranges from 7% to 18%.1-4 A study by Oni et al.,5 on the preva- lence, management, and burden of asthma revealed that asthma affects all age groups, races, and sex. A population-based study showed that more boys are usually affected than girls in the early decades of life, how- ever, the prevalence becomes equal by the third decade of life, and afterward. More women were reported to be affected after the third decade. Symptom relief, reduction in the use of on-demand inhalers, improvement in activ- ities and lung function are the day-to-day asthma control achievements.6 The absence of asthma exacerbations ensures the mini- mization of future risks by preventing accelerated decline in lung function and side-effects from medications over time.6 Progress is being made in the under- standing and management of asthma, the inflammatory nature of the disease, use of steroids, and add-on of inhaled bronchodila- tor combined with steroids, devices to deliver the medications appropriately, and appreciation of the value of self-manage- ment education.1,7 In the treatment of airway disorders, bronchodilators are central in managing most chronic obstructive pulmonary dis- eases and are critical in managing asthma.8 The recent update by GINA9 indicates the consideration of low dose ICS-formoterol as controller medication for the manage- ment of bronchial asthma or ICS-SABA as an alternative in countries where ICS-for- moterol is unavailable, low-dose. According to Boros and Martusewicz- Boros10 airway reversibility is a test com- monly used in diagnosing obstructive lung disease; its result can be used as a differen- tial diagnosis between asthma and chronic obstructive pulmonary disease. Chung et al.11 identified FEV1/FVC70% pre- dicted value.9 Several studies have been conducted to understand the effect of body position on pulmonary function. The most recent, a sys- tematic review by Katz et al.,12 reported higher FEV1, FVC, FRC, Imax, and PEF values in most studies involving healthy subjects or patients with lung, heart, neuro- muscular disease, or obesity in a more erect Healthcare in Low-resource Settings 2022; volume 10:10251 Correspondence: Eniola Awolola Oladejo, Department of Physiotherapy, College of Health Sciences, University of KwaZulu-Natal, Block E-5 University Road, Westville, Private Bag X54001, Durban, 4000, South Africa. Tel.: +27679542461, +2348056333106 E-mail: 220068603@stu.ukzn.ac.za Key words: IFT; asthma; PFT; ACT; AQLQ. Acknowledgements: We hereby thank all the physio- therapists and medical doctors at Lagos State University Teaching Hospital, Ikeja, Lagos, for their contribution to the study’s success and, most impor- tantly, the participants for their voluntary participa- tion. Our profound appreciation also goes to Dr. Olufunke Adeyeye and Dr. Olufemi Ojo of Lagos State University Teaching Hospital, Ikeja, Lagos, for their professional advice in writing and reviewing this manuscript; to Miss Kemi and Miss Laide for their support in conducting the pulmonary function test; and to Miss Amodeni Ayomopewa for her edito- rial input. Contributions: EAO developed the study idea; EAO and SMS developed the title; and both contributed to the study design. All authors were involved in designing the qualitative and quantitative aspects of the study. EAO was responsible for drafting the ini- tial manuscript. SMS was responsible for editing and critical review of the manuscript. Both authors read, critically revised, and approved the final version of the manuscript. The views expressed in this study are strictly the views of the authors and not of the insti- tution or any other group of people. Conflict of interest: The authors declare no conflict of interest. Funding: EAO funded the study. No funding was received from any external source for the study. The study design, writing the manuscript, data collection and analysis are independent of the institutions used for the study. Access to Protocol: https://pactr.samrc.ac.za/ Researcher/ManageTrials.aspx The protocol was registered on the 1st of May 2020 with identifier number PACTR202005807526130 and the trial organization is UKZN. Availability of data and materials: The corresponding author will make available the datasets for the study upon reasonable request. However, the findings from the study will be made available to participating researchers as required by law. Ethics approval and consent to participate: This study has been approved by the Biomedical Research Ethics Committee of the University of KwaZulu Natal (South Africa) (Ethics Number: BREC/00001883/2020), and by the Human Research Ethics Committee of Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria, West Africa (LREC/06/10/1428). The study is registered with ClinicalTrial.gov with registration number PACTR202005890624077. Informed consent: A written and signed informed consent will be obtained from all participants recruit- ed for this study through a third party that is inde- pendent of the study team. The consent form is designed by the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BREC) according to the WMA Helsinki Declaration and good clinical practice (GCP). During the trial, the PI will communicate in writing to the RECs in the event of the need to modify or amend the proto- col, especially the inclusion or exclusion criteria of the study. Received for publication: 24 October 2021. Revision received: 13 December 2021. Accepted for publication: 11 January 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Healthcare in Low-resource Settings 2022; 10:10251 doi:10.4081/hls.2022.1051 [Healthcare in Low-resource Settings 2022; 10:10251] [page 1] Non -co mmerc ial us e o nly position. For subjects with tetraplegia, spinal cord injury, FVC and FEV1 were higher in supine vs. sitting.12 Interferential therapy (IFT) involves the application of two medium frequency cur- rents to the skin in such a way that the cur- rents “interfere” with each other to produce a “beat” frequency.13 The difference between the medium frequency currents is termed the beat frequency, and the body recognizes it as the required low-frequency current. Interferential therapy induces expectoration by making sputum on the bronchi surface mobile and reduces shoul- der stiffness, muscular fatigue, and myalgia in the chest and upper back regions.14 Interferential current (IFC), a non-inva- sive treatment modality, is often used to induce analgesia, elicit muscle contractions, and reduce oedema.15-17 For many years, the effectiveness of asthma medications has been assessed by measuring their impact on expected clinical outcomes such as expira- tory flow rates, symptoms, the need for other medications, and airway responsive- ness.18 Although of great importance, none of the measurements indicates whether the patients can function better in their day-to- day lives.18 Aim of the study The overall aim of this study is to deter- mine the effect of IFT applied in 45° or 90° long sitting with a bronchodilator (short or long acting) on asthma control, quality of life, and selected pulmonary variables of asthmatic patients attending the respiratory clinic of Lagos State University Teaching Hospital, Ikeja, Lagos. This study is designed to investigate the efficacy of a non-invasive therapeutic modality on airway reversibility, asthma control, quality of life of bronchial asthma (BA) patients in 2 different body positions using the GLI (LLN) 2012 reference equa- tion for asthma classification and the 2019 Pan African Thoracic Society (PATS) and European Respiratory Society guidelines for the validation of spirometry test results. The outcome from this study may provide a non-invasive solution to the bronchospasm frequently experienced during an asthma attack. Hypothesis H0 Interferential therapy (IFT) applied in 45° or 90° long sitting will have no signifi- cant effect on airway reversibility, asthma control, and bronchial asthma patients’ quality of life. Delimitation This study will be delimited to 48 bronchial asthma patients attending the Lagos State University Teaching Hospital, Ikeja, Lagos respiratory clinic. Significance of the study It is expected that the outcome of this study will establish the relationship among interferential therapy, bronchodilators, and body position in asthma control, asthma quality of life, and selected pulmonary vari- ables of patients living with bronchial asth- ma. It is expected that this study will pro- vide substantial evidence on airway reversibility in bronchial asthma using IFT. Materials and Methods Study design The study is a parallel, 12-week ran- domized control trial and will involve four (4) intervention groups and four parallel placebo control groups. Participants The participants for this study will con- sist of male and female adult bronchial asth- ma patients aged 18 and above attending Lagos State University Teaching Hospital (LASUTH), Ikeja, Lagos, Nigeria in West Africa. The inclusion criteria involve patients with bronchial asthma aged 18 and above attending the respiratory clinic of LASUTH. The exclusion criteria involve patients with other types of COPD other than bronchial asthma, hypersensitive to B2 ago- nist, patients with a cardiac pacemaker, who have had recent surgery, supplemental oxy- gen therapy, or with cardiac conditions, and patients with psychological impairments. Participants who meet the required cri- teria will be asked to read and sign an informed consent approved for this study by the appropriate institutional review board. Setting Patients with bronchial asthma attend- ing the respiratory clinic of Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria, will be recruited for the study. The hospital is a tertiary health facil- ity within the state and receives referrals from within and outside the state. Article Figure 1. F tests -MANOVA: Repeated measures, within-between interaction. [page 2] [Healthcare in Low-resource Settings 2022; 10:10251] Non -co mmerc ial us e o nly Sample size The pulmonary function test is the pri- mary outcome of interest for the study and the expected clinically-relevant difference for pulmonary rehabilitation in various body positions using LLN and GLI refer- ence equation proposed by Quanjer et al.19 Therefore, the sample size (N) will be deter- mined using the G-Power statistics soft- ware. The power is selected at 95% =0.95, confidence level at 5% =0.05 and effect size of 0.35 (Figure 1). Randomization and blinding The contact numbers of participants will be randomly extracted from the database on respiratory patients attending the Lagos State University Teaching Hospital Ikeja respiratory clinic (Figure 2). A bulk text message captioned “Invitation to a study on ASTHMA″ will be circulated using the Luxury bulk SMS platform. Respondents will be assessed for eligibility, and those that meet the inclusion criteria will participate in the study while those who have any of the exclusion criteria will be excluded. Participants will be randomly selected by simple randomization using a computer software program randomization table.20 The software program (www.randomiza- tion.com) will be used to allocate partici- pants into study group A and control group B. Group A was further assigned to sub- group x, and y, while group B was assigned to subgroup e, and f. Subgroup x and e rep- resents participants on SABA, while Subgroup y and f represents participants on LABA. Participants were randomly assigned to a final group of xa, xb, ya, yb, ea, eb, fa, and fb, with ‘a’ and ‘b’ connoting 45° and 90° long sitting respectively. Procedure for data collection Forty-eight (48) subjects will be recruit- ed for this study. The subjects will be ran- domly assigned into two major groups of twenty-four (24) subjects per group, two (2) subgroups of twelve (12) subjects per sub- group, and eight (8) final groups of six (6) subjects per group. Assessment The subjects’ medical records will be adequately screened for possible contraindi- cations to the study. Baseline respiratory parameters will be assessed using the Koko PFT spirometer. The Asthma Control Test Questionnaire and Asthma Quality of Life questionnaire will be administered to the control and study groups at the beginning of the study and at two-week intervals for the 12 weeks of the study. Baseline spirometry will be Article Figure 2. Recruitment and randomization of participants. [Healthcare in Low-resource Settings 2022; 10:10251] [page 3] Non -co mmerc ial us e o nly [page 4] [Healthcare in Low-resource Settings 2022; 10:10251] conducted on the two groups before and after the commencement of the study. The interferential unit “Nu-Tek E-Stim Pro MT1022970” will be used for the study intervention. The treatment period will be increased by two minutes with each appli- cation, up to a total application time of 20 minutes. Assessment tools Spirometry assessment The assessment will be conducted by a spirometrist certified by the Pan African Thoracic Society. A portable spirometer (Koko SX 1000 Standalone Version 7 Pneumotach) will be used to carry out this assessment. Daily calibration of the device will be done using a 3.0-litre syringe. A brief description of the assessment proce- dure, including technical steps to obtain pulmonary function data and variables, will be explained to each subject. After 2-3 tidal breaths, the subject will be asked to inhale deeply to total lung capacity and then exhale rapidly (without any pause) through a disposable mouthpiece until as much air as possible has been expelled from the lungs. The test will be performed in a sitting or standing position. The assessments will be repeated three times after adequate rest. The maximum number of attempts permit- ted will be 8. After fulfilling the acceptabil- ity and repeatability criteria, the two best curves will be selected. The average values of the forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) will be recorded.21 Intervention Participants will be briefed about the nature, effect, and benefit of the study. They will be encouraged to clarify issues regard- ing the study. All participants will be required to give a written informed consent before participating in the study. Participants will be randomly assigned into two groups: study group (Group A) and control group (Group B). Interferential ther- apy will be demonstrated to the study group alone. The Asthma Control Test, Asthma Quality of Life Questionnaire, and spirome- try score will be measured and recorded before intervention in both groups. Reassessments will conducted at the end of the 2nd, 4th, 6th, 8th, 10th, and 12th weeks of the study intervention. The study group (Group A) will receive interferential therapy; this modality selec- tion is only acceptable in the absence of car- diac disease history.22 In the absence of such a history, the subjects will be divided into two subgroups and labeled x and y. Subgroup ‘x’ will be allowed to use 400ug of SABA delivered in metered doses via a spacer4-6 hours before the study, while sub- group ‘y’ will be allowed to use 24ug of LABA delivered in metered doses via a dry- powder inhaler within 24 hours of the study.23 In both cases, the inhaler technique, as described by Basheti et al.24 will be used to demonstrate the procedure to the partici- pants. The intervention will be conducted with participants in a long sitting position, at an angle of 45° and 90° representing labels ‘a’ and ‘b’ respectively. In both inter- vention positions, an electrode will be placed bilaterally over the upper limit of the trapezius on the upper back and the other two anteriorly over the lower ribs.22 The final group of participants to undergo the intervention will consist of ‘xa,’ ‘xb,’ ‘ya’ and ‘yb.’ If the subject experiences respira- tory difficulty during the intervention, the procedure will be discontinued. With a 4,000 Hz base current, the interferential cur- rent range will be set between10 to 150 Hz and initially applied for 10 minutes, while carefully monitoring the patient’s condition during the treatment period. If the patient shows any sign of distress during the treat- ment, the current will be turned off. As long as the subject does not experience any dis- tress with the IFC application, the treatment period will be increased by two minutes with each application, for up to 20 minutes. Participants in the control group (Group B), in addition to the baseline pulmonary function test, will also receive free muscu- loskeletal assessment and counselling on asthma. They will be divided into two sub- groups and labelled ‘e’ and ‘f.’ Participants in subgroup ‘e’ will be allowed to use 400ug of SABA delivered in metered doses via a spacer 4-6 hours before the study, while subgroup ‘f’ will be allowed to use 24ug of LABA delivered in metered doses via a dry- powder inhaler within 24 hours of the study.23 The intervention will be conducted with participants in a long sitting position, at an angle of 45° and 90° representing labels ‘a’ and ‘b’ respectively. The final group of participants to undergo the inter- vention will consist of ‘ea,’ ‘eb,’ ‘fa’ and ‘fb.’ In both cases, the inhaler technique, as described by Basheti et al,24 will be used to demonstrate the procedure to the partici- pants. They will be asked to maintain their respective positions for 20 minutes. If the subject experiences respiratory difficulty, the procedure will be discontinued. Outcome measures/instruments i) Asthma Control Test (ACT); ii) Asthma Quality of Life Questionnaire (AQLQ); iii) Spirometer (Koko SX 1000 Standalone Version 7 Pneumotach); iv) Interferential Therapy Machine (Nu-Tek E- Stim Pro MT1022970). Description of outcome measures/instruments Asthma Control Test (ACT) The asthma control test is a self-admin- istered 5-item questionnaire developed for assessing asthma control level. It evaluates the most recent four-week period. Each item is scored between 1 and 5, with a total score ranging from 5 to 25. An ACT score of 25 indicates that asthma is “controlled” whereas a score between 20 and 24 shows partially controlled asthma and a score of <20 indicates “uncontrolled” asthma.25 Asthma Quality of Life Questionnaire Standardised (AQLQS) The standardized version of the Asthma Quality of Life Questionnaire (AQLQ) is a 32-item questionnaire (self-administered or clinician administered) with five domains, developed to measure the functional, physi- cal, emotional, occupational, and social problems that are most troublesome to adults with asthma.18 The maximum score obtainable is 7.0, which translates to no impairment. The minimum score is 1.0, indicating severe impairment, 4.0 is the mid-range score, and indicates moderate impairment.18 The Asthma Quality of Life Questionnaire standardized version will be used to monitor the difficulty the subjects encounter in activities of daily living as a result of asthma. Spirometer Koko SX 1000 Standalone Version 7 Pneumotach, a portable lightweight and comprehensive diagnostic tool, will be uti- lized to conduct the pulmonary function test. The Koko Legend II spirometer has a built-in thermal printer and a touch screen display. It can perform FVC, Pre vs. Post, and SVC tests. Test data and patient infor- mation are stored directly on an internal SD card that can be replaced and re-used. All the stored information can be downloaded via a USB cable onto a PC for backup or storage. This device supports daily calibra- tion checks, complies with ATS-ERS 2005, has several predicted authors, and includes GLI-2012. Daily calibration of the device will be conducted using a 3L syringe.26 The participant’s condition can be shown by the ratio of the measured value to the predicted value. Flow rate-volume chart, volume-time chart display, data mem- ory, delete, upload and review, trend chart display, scaling (calibration), information prompts when volume or flow goes beyond the limits are features available on the device. Bronchodilators The administration of bronchodilators will be primarily through inhalation devices Article Non -co mmerc ial us e o nly [Healthcare in Low-resource Settings 2022; 10:10251] [page 5] to deliver the drug to the lung bronchioles in metered doses. Inhalation devices come in all shapes and sizes, but critical is maximiz- ing the amount of drug reaching the bron- chioles. The best way to achieve maximum bioavailability is by fully exhaling, placing the inhaler in the mouth, and taking a full inhalation. After the patient has inhaled completely, it will be followed by 10 sec- onds of no breathing to wait for the medicine to dissipate into the lung space. A slow exhalation back to normal breathing will be advised.27,28 The eight-point inhaler technique as described by Basheti, Natsheh24 will be used to deliver bron- chodilators and pre-BD reversibility testing in metered doses. Interferential unit The Nu-Tek Electrotherapy Machine E- Stim Pro MT1022 provides low and medi- um frequency outputs from a single unit. The currents available on the Nu-Tek Electrotherapy Machine E-Stim Pro MT1022 include Interferential (2 and 4- pole), Russian, Diadynamic, TENS, Sinusoidal, Faradic, Galvanic, Interrupted Galvanic, Trabert, and Medi-Wave.29 The Nu-Tek E-Stim Pro MT1022 will be used to deliver interferential current by generating a beat frequency range of 10-150hz from two medium frequency currents undulating at a base frequency of 4000Hz to 4100Hz.14 An interferential current will be activated with two electrodes, one placed posteriorly at the upper border of the trapezius and the other anteriorly below the ribs. A beat frequency will be generated at the point of intersec- tion, resulting in relaxation of the smooth muscles, resolution of pain, and mobiliza- tion of secretions.14 Data analysis The Statistical Package for Social Sciences (SPSS Inc, Chicago, II) version 26.0 for the Windows package program will be used to analyse data. The results will be summarized using descriptive statistics of mean, standard deviation, frequency, and percentages. Bar charts, pie charts, and his- tograms will be utilized for pictorial illus- tration. A multilevel analysis of variance (ANOVA) will be used to compare the out- come variables [body position (45 degrees long sitting and 90 degrees long sitting), pulmonary function variables (FEV1, FVC, FEV1/FVC), asthma control test (ACT), and the standardized Asthma Quality of Life Questionnaire (AQLQ)] among each group, and the dependent t-test will be used to compare the pre and post-test results while the independent t-test will be used to compare the outcome variables across the two groups. The level of significance will be set at p0.05. Harms This study carries minimal risks. The procedures are not life-threatening and should not cause any harm or negative effect. The effects may include temporary muscle soreness, increased heart rate, blood pressure, sweating, and dizziness. Necessary care will be taken to prevent the occurrence of an adverse event. However, in case of a report of serious adverse events (e.g., comorbidities, injuries, persistent excruciating pain, dizzy spells, headache, etc.) after intervention or at any point dur- ing the trial, we would consider unblinding the participant to the intervention for his/her safety. Additionally, the participants will be instructed to report any adverse events to the PI or the physiotherapist supervising their group. To ensure adequate supervision and safety, the number of participants per group in a day will be limited to a maximum of 3. Arrangements have been made with the Accident and Emergency unit of the hospital where the research will be conduct- ed to provide a standby medical team. However, the University of KwaZulu-Natal insurance scheme on clinical trials fully covers participants in this type of study. Discussion The relationship between medication- induced airway reversibility and reversibili- ty obtained through electrophysical modali- ties is still not well justified. Furthermore, the relationship between the mode of deliv- ery of electrophysical agents and the recov- ery pattern in bronchial asthma is yet to be fully understood. A study by Karashurov et al.30 on pro- grammed electrostimulation of the sinocarotid nerves implanted to 78 patients with bacterial asthma for six years was reported to have prevented the majority of asphyxia attacks, reduced their frequency 2.7-fold, and the need for medications 2.7- 3.4-fold. Aweto et al.31 in a study of the effect of IFT on the cardiopulmonary parameters of 42 BA patients for six weeks reported a sig- nificant improvement in systolic blood pressure (p=0.004), forced expiratory vol- ume in one second (p=0.02), forced vital capacity (p=0.04), and peak expiratory flow rate (p=0.007), while the control group had significant reductions in pulmonary param- eters. There were significant improvements (increases) in the ACT score (p=0.0001) and AQLQ (p=0.001). Mohammed and Elyazed32 studied thir- ty Egyptian children aged 9-15 with BMI 18.5 to 24.9 kg/m2, who had asthma. The pre- and post-treatment variables revealed a significant improvement in pulmonary functions in favor of laser puncture therapy and interferential therapy over diaphrag- matic exercise. Although studies by Aweto et al.,31 Karashurov et al.,30 and Mohammed and Elyazed32 identified the effect of an electro- physical agent in the management of asth- ma, their findings did not ascertain the pos- sible effect of the medication used by the patients during the procedure. Consequently, it is expected that this study’s outcome will further reveal the effect of the electrophysical modality on the symptoms frequently experienced by asthma patients who are on short or long-acting bron- chodilator medication. Finally, it is expected that the findings of this study could serve as guideline for the management of BA with electrophysical agents and would further support the cost- benefit of asthma management in Nigeria and other low-income countries. References 1. Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program. The global burden of asthma: Executive summary of the GINA Dissemination Committee report. Allergy 2004:59:469–478. 2. 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