Study design
This study is a randomized controlled trial with three groups: sensory threshold stimulus group (Group A), motor threshold stimulus group (Group B), and sham EA stimulus group (Group C). This trial was approved by the ethics committee of Guangdong Provincial Hospital of Chinese Medicine (BF2022-128-01). Before randomization, written informed consent will be obtained from all participants prior to their involvement. Primary outcome measures will be evaluated at baseline, 4 and 8 weeks, and 1-month follow-up. Secondary outcomes will be assessed at baseline and post treatment. Outcome assessors and statisticians will be blinded in this study. A flowchart of the study protocol is shown in Fig. 1. This protocol is compiled in line with the Standard Protocol Items [21]: Recommendation for Interventional Trials (SPIRIT) statement requirements (Table 1).
Participants
In this trial, patients with PFP sequelae will be recruited and the research will be conducted in the Second Affiliated Hospital of Guangzhou University of Chinese Medicine. Patients will be included if they meet the following criteria.
Inclusion criteria
Participants will be included if they meet the following criteria:
- Meet the criteria of peripheral facial paralysis [22].
- Patients diagnosed with peripheral facial paralysis more than 3 months before screening.
- Unilateral peripheral facial paralysis.
- Male or female patients aged between 18 and 65.
- Voluntarily participating in this trial with a written informed consent form.
Exclusion criteria
Participants with the following conditions will be excluded:
- Central facial paralysis, peripheral facial paralysis in acute stage.
- Primary and secondary neurological diseases, such as diabetic.
- Patients with serious acute or chronic organic diseases and systematic diseases.
- Patients with coagulopathy.
- Pregnant or nursing patients.
Elimination criteria
- Patients included and do not meet the inclusion criteria.
- Patients who are not excluded and meet the exclusion criteria.
- Eligible participants who are not on any clinical interventions.
Withdrawal criteria
- Poor compliance to the treatment (cannot finish 8-week treatment for personal reasons).
- Patients experiencing severe adverse events, complications, or special physiological changes.
- Voluntary dropout.
Randomization and allocation
After screening for eligibility, all patients will be randomly allocated to three groups in a 1:1:1 ratio by an independent investigator. SPSS for Windows (Version 26.0; SPSS Inc., Armonk, NY, USA) will be used to create the randomization sequence. After that, random numbers will be placed in sealed opaque assignment envelopes for allocation concealment and assigned to the patients.
Blinding
The participants, outcome assessors, and statisticians will be blinded to treatment allocation. All participants will be informed that they have an equal opportunity for allocation to the three groups before enrollment. To prevent communication among patients, they will be treated separately and throughout the whole treatment, patients’ eyes will be covered with a blindfold to prevent them from observing the procedures. All the treatments will be performed by trained and experienced acupuncturists. The acupuncturists, patients, assessors and statisticians are independent and not allow to communicate allocations information among one another.
Interventions
All the treatments will be conducted in the acupuncture and moxibustion department by acupuncturists, who have at least 3 years clinical experience and will administer the treatments strictly following the detailed protocol. During treatments, it is not permitted to use any medications or other therapies for PFP, if do so, it should be documented. Generally, patients in three groups will receive 20 sessions of EA stimulation on the affected side twice a week for a total of 8 weeks. Each session will last about 30 minutes after needling at local and distal acupoints below: Sibai (ST2), Dicang (ST4), Hegu (LI 4) and Yuji (LU 10). Locations of acupoints were conformed to the WHO standard [23] (Table 2 and Fig. 2).
Table 2
Acupoints
|
Side
|
Locations
|
Hegu (LI 4)
|
unaffected side
|
On the dorsum of the hand, radial to the midpoint of the second metacarpal bone
|
Yuji (LU 10)
|
unaffected side
|
On the palm, radial to the midpoint of the first metacarpal bone, at the border between the red and white flesh
|
Sibai (ST 2)
|
affected side
|
On the face, in the infraorbital foramen
|
Dicang (ST 4)
|
affected side
|
On the face, 0.4 cun lateral to the angle of the mouth
|
Note: 1 cun (≈ 20 mm) is defined as the width of the interphalangeal joint of patient’s thumb.
Sensory threshold stimulation
In this group, patients will receive EA stimulation at the level of sensory threshold, i.e., the minimal intensity of stimulation that can be perceived. After skin disinfection, sterile adhesive pads will be placed on the acupoints, then needles (0.25×25mm, Hwato, Suzhou, China) will be inserted through the pad. After “deqi” sensation achieving, a Han's Acupoint Nerve Stimulator (HANS-200A, Nanjing, China) will be connected to acupoints, using a continuous wave of 2Hz. Then, we will measure the electrical sensation.In the administration of electrical stimulation, the participants require to inform their physician immediately as long as the first electrical stimulation was detected (sensory threshold, ST) [24]. In this way it conveys natural proprioception by depolarizing sensory and motor nerves without eliciting any muscular contraction [25].
Motor threshold stimulation
The process for this group will be the same as for sensory threshold stimulation. However, the intensity of the current by EA is at the motor threshold level, that is, the minimum stimulus intensity can produce a direct motor response, which may produce involuntary and uncontrolled segmental movement [26], but without any pain.
Sham EA Stimulation
Participants in the sham EA group will receive the same procedure as the treatment group but using non-insertion sham acupuncture through a supporting rubber pad. The needle stays at the rubber pad over the acupoint for 30 min, having mildly shivering to blind participants. The sham stimulation only leads the participants to the feeling of needle, without “de qi” sensation or electrical stimulation.
Outcomes measurements
Primary outcome
The primary outcomes are the changes in House-Brackmann (H-B Grade) and Facial Disability Index (FDI) [27], which will be evaluated at baseline, 4 weeks treatment, after treatment and one-month follow-up. H-B Grade is used to evaluate the severity of facial paralysis based on the facial function at rest and with effort from Grade I (normal function) to VI (total paralysis).
Secondary outcome
Secondary outcomes include electromyography (EMG) and Blink reflex (BR) of facial nerve, which are recorded at baseline (before treatment) and after treatment.
Electromyography of facial nerve
To assess the degree of facial nerve injury, EMG activities will record from bilateral facial muscles by using a conventional electromyograph (Viking Quest, Nicolet, USA) and store in PC for off-line analysis. Stimulating electrode will be placed on the earlobe while 9-mm-diameter Ag-AgCl surface electrodes on temporal branch and buccal branch of facial nerve respectively. For temporal branch recording, the active electrode will be attached to the nasal muscle and the reference electrode to the other side of this muscle. For buccal branch, active electrode will attach to the side of the lip and the reference electrode at the base of the mandible. Ground electrode will be placed on the forehead. Skin impedance is lower than 5kΩ.
Blink reflex
BR is for the assessment of excitability changes at the brainstem inter-neuronal level. The cathode of the stimulating electrode will be placed on the supraorbital nerve (SON) while the anode place on 3cm above the skin of frontal bone, and the EMG was recorded from O.oculi of bilateral side in patients.
Follow-up
There will be one follow-up after the intervention period. The researchers will contact the participants via phone or WeChat app for successful follow-up.
Adverse events
Acupuncturists need to report and record any acupuncture-related adverse events (AEs), such as local bleeding, hematoma, fainting, local infection, unbearable prickling, or other discomfort after treatment. Severe AEs will be reported to the Research Ethics Committee within 24 hours. REC will provide medical advices to research team for evaluate the suitability of participant in this trial. AEs recording is weekly from week 1 to week 8.
Data collection
Data from this trial will be collected in the case report form (CRF) by two research assistants, including the base characteristics of all patients, the evaluation of primary outcome, the results of secondary outcome, and the AEs. The consent forms will be stored separately from the CRF. Two independent researchers blinded to the group will input the CRF data into an Excel spreadsheet, then cross-check the data. CRF and electronic data will be stored in a secure locker and encrypted computer, only authorized researchers will have access to all documents.
Sample size
In this study, PASS (version 15.0) will be used to calculate the sample size, which based on the results from our pilot study analysis. The values of differences mean and standard deviation for H-B Grade of EA and sham EA group are − 1.60 ± 0.55, -0.80 ± 0.45, respectively. According to the one-way analysis of variance F-test, the type I error is 0.05 and the power is 90%. It is determined that there should be at least 11 patients in each group. If the dropout rate is 15%, then 39 patients are needed in the trial (13 patients per group). The values of differences mean and standard deviation for FDI scores of EA and sham EA group are 5.60 ± 2.79, 2.60 ± 0.89, respectively. According to the one-way analysis of variance F-test, the type I error is 0.05 and the power is 90%. It is determined that there should be at least 18 patients in each group. The dropout rate is considered to be 15%, and thus 66 patients are required to conduct this study (22 patients per group). According to the calculations above, a larger sample was chosen.
Statistical analysis
Data analyses will be performed on the basic of intention-to-treat (ITT) principle. Missing data will be replaced by the data from the latest assessment. SPSS for Windows (Version 26.0; SPSS Inc., Armonk, NY, USA) will be used to analyze data. Quantitative results will be described by the mean, standard deviation and median, while qualitative results will be expressed as total number and percentages. The chi-square test will be used to compare H-B Grade between groups. For FDI scores, the repeated measures method will be used, and post hoc comparisons will be evaluated with the Bonferroni test. The Wilcoxon rank-sum test will be used to compare ranked data and the independent samples t-test for secondary outcome measures to analyze continuous variables. A p-value of < 0.05 will be considered statistically significant.
Ethics and dissemination
This study conforms to the principles of the Declaration of Helsinki and relevant ethical guidelines. This study has been approved by the Institutional Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (BF2022-128-01) and also registered with an identifier (ChiCTR2200062310) at Clinicaltrials.gov in August 2022.Written informed consent will be obtained from patients prior to enrollment in the study. The outcomes of the trial will be disseminated through peer-review publications.