ACUPOINT TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION IN HOSPITALIZED COPD PATIENTS WITH SEVERE DYSPNOEA: STUDY PROTOCOL FOR A RANDOMIZED CONTROLED TRIAL

Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a major cause of hospital admissions and dyspnoea is its main symptom. Some studies have concluded that a new modality of acupuncture called Acupuncture transcutaneous nerve stimulation (acuTENS) could reduce dyspnoea in COPD patients by increasing beta-endorphin levels, however those trials have mainly been conducted on patients with stable condition. This study aims to determinate if the administration of acuTENS can reduce dyspnoea in patients hospitalized for AECOPD. Methods A multicentric randomized control trial with patient- and assessor-blinded will be conducted. A sample of 60 patients will be randomised to receive 45 minutes of either real acuTENS or sham acuTENS treatment once a day during 5 consecutive days. The trial will be conducted at the “Hospital del Mar” of Barcelona (Spain) and the “Hospital Sant Joan de Déu de Manresa” in Manresa (Spain). The Borg scale at baseline, and day 1 to 5 will be the primary outcome. Secondary outcomes will be the duration of the hospitalization, quantity of drugs administrated, expiratory peck flow adverse effects and mortality and readmissions at 3 months. Discussion AcuTENS is non-pharmacological, non-invasive and cheap intervention. This trial will help to understand acuTENS potential role in the treatment of AECOPD.


Background
Chronical obstructive pulmonary disease (COPD) is characterized by persistent and progressive airflow limitation associated with a chronic inflammatory response in the airways and the lung parenchyma to noxious particles or gases. (1) COPD is a major cause of morbidity and mortality worldwide and its prevalence is expected to increase over the next decade due to continuous exposure to risk factors and the aging of the population (2). It is estimated that in 2030 COPD will be the fourth leading cause of death globally 3 (3). Currently, the prevalence of the disease in Spain is 10.2% of the population between 40 and 80 years (4).
Dyspnoea, along with chronic cough and sputum production, is one of the main symptoms of COPD. Its severity and magnitude increase as the disease progresses being the main cause of disability and reduced quality of life in COPD patients (5).
Patients may experience periods of acute exacerbation of COPD (AECOPD) defined as " a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, which is acute in onset and necessitates a change in regular medication in a patient with underlying COPD " (6). These can be particularly severe exacerbations requiring hospitalization. In Spain it is estimated that hospitalizations for AECOPD have an average cost of 344.96 euros per person per day (7), most of which is due to stays in hospital. These exacerbations are associated with a 12% of mortality and a 35 % of readmissions up to 3 months after discharge (8).
Treatment of AECOPD includes bronchodilators, corticosteroids, antibiotics, oxygen therapy and non-invasive mechanical ventilation (9). In the case of severe dyspnoea oral or parenteral administration of opioids are recommended, although these have side effects and can cause respiratory depression (5). However, dyspnoea remains a major symptom in patients hospitalized for an AECOPD (7).
The acupoint transcutaneous electrical nerve stimulation (AcuTENS) is a modern technique based on traditional acupuncture. It consists in the stimulation of acupuncture points using transcutaneous electrical nerve stimulation (TENS) instead of needles, which makes it a very easy to learn, non-invasive method without the traditional acupuncture adverse effects such as infections or puncture of internal organs (10).
Several clinical studies using AcuTENS in patients with COPD have recently been published. All studies have used the stimulation of the acupuncture point named Dingchuan (EX-B1), traditionally used to treat dyspnoea. In those studies, a decrease in dyspnoea and an increase in FEV 1, β-endorphin level and quality of life have been observed (11)(12)(13). However, these studies have been conducted on patients in stable conditions and little is known about the possible effect of this technique in patients with an AECOPD. Only one case study has been published to the date suggesting possible benefits on the shortness of breath besides an increase in the level of oxygen saturation and β-endorphins (14).
The objectives of this study are to determine if the use of AcuTENS at the Dingchuan point (EX-B1) could be beneficial for patients hospitalized for AECOPD by reducing dyspnoea, days of hospitalization and consumption of regular medication. Moreover, we will assess possible adverse effects of this technique and its effect on mortality and readmissions at 3 months after discharge.

Trial Design
Multicentric, randomized controlled trial with blinded patients and assessors with a 1:1 allocation and two parallel groups.

Study setting :
The study will be performed at the "Hospital del Mar" in Barcelona (Spain) and the "Hospital de Sant Joan de Déu de Manresa" in Manresa (Spain).

Participants:
The study subjects will be patients admitted at the study centres for an AECOPD.
Participants will be recruited at the time of their admission by the pulmonology service and hospital emergency staff using the following inclusion: (1) patients aged between 45 and 75 years, with a diagnosis of COPD according to the GOLD guidelines, (2) patients with one episode of hospitalization for COPD exacerbation in the past year, but not more than three episodes, (3) smoking habit history of more than 10 packages-year, (4) patients able to correctly understand and answer the modified Borg scale, (5) patients with an initial degree of dyspnoea with a score of at least 5 in the modified Borg scale at recruitment, (6) patients recruited for the study during the first 48 hours of their hospitalization, (7) patients who agree to participate in the study and sign the informed consent.
Exclusion criteria will be: (1) patients with any contraindication for transcutaneous electrical stimulation (patients with pacemakers, skin injury in the application area ...), (2) patients with any cardiovascular, neurological or psychiatric disease that may affect the perception of dyspnoea.

Interventions:
In both groups the Dingchuan point (EX-B1) will be localized bilaterally at 0.5 "cun" from the midline between the posterior spinous processes of C7 and T1. Afterwards a conductive plastic sheet between the skin and the electrodes will be placed. These sheets have a hole of about 0.5 cm in diameter, which will coincide with the point above. Finally, the electrodes will be fixed with tape.

AcuTENS group (experimental):
The stimulation is performed using a portable TENS electrostimulation device (Sale & Sevice TN23) that uses a biphasic rectangular wave with a frequency of 2Hz and a pulse width of 200 mS. The stimulation will be achieved using the highest intensity tolerated by the patient without pain.
TENS simulated group (control): This group will have electro stimulators of the same make and model as the experimental group, but that have been modified to have no electrical outlet, even though the screen will light up and display the same data as in the 6 unmodified device. Patients in this group will be informed that, due to the frequency of stimulation, it is unlikely that they will feel the electric stimulation.
In both groups, the session will last 45 minutes and will take place during a maximum of five consecutive days or until the patient is discharged.
If the acuTENS stimulation produces any kind of discomfort, the intensity of the current being applied to the patient will be reduced. If for any reason a treatment cannot be administered or is administered differently from the original protocol (example: only 30 min treatment because the electrostimulation device had no battery) this will be reported.
Any discomfort or skin reaction will be reported as an adverse event.
The interventions will be performed by physiotherapists or physicians with a minimum of one year of clinical experience, who have been trained in the handling of the two treatment protocols. There will be a pre-pilot test to detect potential problems and ensure the adequacy of the implementation of the protocols.
Adherence to the treatment will be reported. No special stages for improving adherence will be taken since all patients will be hospitalized in the participating centres.
Both groups will receive the standard treatment for patients with AECOPD (bronchodilators, steroids ...) according to medical criteria, as well as the treatment with acuTENS or simulated acuTENS. No treatment is prohibited.

Outcomes
The primary outcome of this trial will be dyspnoea using the modified Borg Scale.
Evaluators will show a printed Borg scale to patients and explain the meaning of each punctuation, then patients will be asked to rate their dyspnoea. Data will be assessed at baseline and after each treatment session (day 1 to day 5). The modified Borg Scale is a valid and reliable assessment tool for dyspnoea in patients with an AECOPD (16). Secondary outcomes will be (1) number hospitalization days, (2) quantity of drugs administered during hospitalization, (3) adverse events during the 5-day treatment, (4) peak expiratory flow at each day (day 1 to day 5) and difference from baseline to day 5 using a peak flow meter, (5) blood gas analysis (PaO2, PaCO2, arterial blood pH, bicarbonate and SaO2) at each day (day 1 to day 5) and difference from baseline to day 5 and (6) mortality, relapses and readmissions during the first three months after discharge.
Data will be collected using a standard form.

Participant timeline
Participant timeline is described in figure 1.

Randomization and allocation:
Participants will be randomly assigned to the acuTENS or sham acuTENS group with a 1:1 allocation using a computer-generated randomisation list. A blocked randomisation list will be generated for each centre by the main author, who will not be involve in the recruitment or assessment.
Randomisation lists will be kept using electronic key and only will be available to the persons responsible for administering the treatments.
Once participants give consent for participation a consecutive number will be assigned by the head of recruitment, the staff responsible of administrating the treatment will match the patient's number with the randomization list to define patient's allocation.

Blinding
Trial participants, outcome assessors and usual care providers will be blinded during the trial, only the physiotherapists who will perform the acuTENS or sham acuTENS procedure will know patient's allocation. The medical staff will not be present during the application of technology to ensure that they remain blinded to allocation.
Sample size 8 Given that the significant difference in clinical minimally dyspnoea measured by the Borg scale for patients with COPD exacerbation is 2 (15), a common standard deviation of 2.6 and assuming an α error of 0.05, a β error of 0.2 and a 10% of losses, it is calculated that we will need to recruit 60 patients for this study.

Statistical methods
There will be a descriptive analysis of the demographic data using means and standard deviations (mean ± SD) for continuous variables and absolute values and percentages for qualitative outcomes.
For the comparative analysis between the two groups, continuous outcomes will be analysed using mean differences with a 95% confidence interval with a t' Student test or Mann-Whitney U depending on the distribution of these. For qualitative outcomes risk ratio will also be used with a confidence interval of 95% and test χ2.
The main analysis will be done by intention to treat, but there will be another per-protocol analysis for patients who have received at least three interventions. Significant difference will be considered as a value of p <0.05.
In the case of significant baseline differences between the two groups there will be an adjusted analysis for these outcomes. All patients will be informed about the nature of the study, its objective, and the possible adverse effects of the treatments, as well as their voluntary participation. All patients must sign an informed consent document. The patients will be able to leave the study whenever they want without any detriment to their health care.

Discussion
The data collected during the study will be treated in accordance with the LOPD, Regulation (EU) nº2016 / 679 of the European Parliament and European Council on data protection (RGPD) that came into force on May 25, 2018.
Data monitoring is not needed as the treatment used is expected to have low safety risk.
For the same reason, no interim analysis or stopping guidelines are considered. No 10 additional insurance was needed for this trial since the TENS device is regularly used in the rehabilitation department.
Results of the trial will be disseminated via publication.

Consent for publication
Not applicable.
Availability of data and material Not applicable.

Competing interests
Authors declare no financial or competing interests.

Funding
This work was supported by a grant from the Professional College of Physiotherapists of Catalonia and the Scientific Society of Acupuncture of Catalonia and the Balearic Islands.

Funders.
Funders had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.
Authors' contributions CF has been responsible for writing the protocol of the study, and the submission of the manuscript. JV helped with the study design and the sample size calculation. All authors contributed to refinement of the study protocol and approved the final manuscript.