Study design:
This is a pilot, single-site, patient-assessor-blinded, placebo-controlled, randomized clinical trial which will be carried out in Shanghai Municipal Hospital of Traditional Chinese Medicine. Eligible patients will be randomly divided into the EA group and the SEA group in a 1:1 allocation ratio. All patients will sign the informed consent before proceeding with the trial. The flowchart of the study process is detailed in Figure. 1.
Figure. 1. Flowchart of this study
Sample size:
This is a pilot study. In the relevant literature, no previous studies have utilized either the same evaluation method as the main solution index, the comparison method or the degree of intervention. Therefore, we are unable to formally calculate a statistical power. The appropriate sample size for a 2-arm pilot study should be more than 12, considering we assume a 20% dropout rate, each group will take 15 cases. We will therefore recruit a total of 30 individuals for this randomized controlled trial (RCT)[13-15].
Recruitment:
This pilot randomized, sham-controlled, patient-assessor-blinded trial will be recruited in the Shanghai Municipal Hospital of Traditional Chinese Medicine. Eligible subjects who have been scheduled for nasal endoscopic surgery for sinusitis with nasal polyps will be invited to participate in this study. Participants will be referred from an ENT (ear -nose-throat) doctor, and then a research assistant will screen the patients and obtain written informed consent. Following the consent, eligible participants will be randomly allocated to either the electroacupuncture group or sham electroacupuncture e group. All participants will undergo a standard operative procedure and receive postoperative treatment. Treatment will be given within 2 hours prior to the surgery, immediately after surgery arrival to the recovery ward and daily treatment following surgery for 3 days. NRS assessments will be conducted after arrival to ward, every hour for 6 hours, and other secondary outcome measurements will be taken once per day until discharge. The assessment schedule is detailed in Table. 1.
Table. 1. Schedule of enrolment, intervention and assessment
Inclusion Criteria:
Patients who meet the following criteria will be included:
1) Patients with an American Society of Anesthesiologists (ASA) physical status I to II;
2) Eligible for nasal endoscopic surgery, including Sinusitis with nasal polyps;
3) Age is 18-60 years old;
4) Capable of understanding and providing responses about the outcome measurement;
5) Agree to participate in the survey and sign a written informed consent form.
Exclusion Criteria:
Patients who meet the following criteria will be excluded:
1) Having chronic pain currently requiring treatment by an opioid or nonsteroidal anti-inflammatory drug medication;
2) Having severe psychiatric disease and cognitive impairment and not able to sign the consent;
3) Having hepatitis B, hepatitis C, HIV or syphilis;
4) Having a history alcohol or drug abuse;
5) Having local or systemic infection;
6) History of acupuncture experience in the past 6 months.
Randomization and Allocation concealment:
The random sequence will be conducted by block randomization using the SPSS version 23.0 software by an independent research assistant. After the participants complete the screening process and baseline assessment, they will be randomly assigned to 1 group in a 1:1 ratio. The random sequence will be kept in the opaque envelopes. The treatment allocation codes will not be revealed before the first treatment. In an effort to minimize breaks in coding, the principal investigator who designed the trial and research personnel who perform the outcome assessments will also be blinded to the treatment assignment.
Blinding:
Before the beginning of treatment, we will tell the participants that they have the same possibility of being assigned to the electroacupuncture treatment or electroacupuncture -like simulation treatment. In order to ensure the implementation of the blinding method, the acupuncturist will require the participant to wear the eye-patch before they receive treatment. Therefore, there is no one would know the treatment allocation before the initial treatment. Only the acupuncturist who performs the treatment will know the group allocation at the time of treatment (the principal investigator, the data analysts, the outcome assessors and statistician) will remain blinded.
Quality control:
The pre-job training and examination of acupuncture treatments will be performed by the principal investigator (Dr. SF Xu) to ensure the quality of this trial. This includes the inclusion and exclusion criteria, location of the acupoints and the depth of needling. In addition, the data management and outcome measures and statistical analysis will be completed by 3 independent researchers.
Intervention protocol:
The electroacupuncture treatment will be performed within 2 hours before surgery, immediately after surgery in the recovery ward and every 24 hours after the surgery for 3 days (5 treatments sessions in total). In each treatment session, every patient will be in a separate space and wear an eye-mask. Acupuncturists must be registered, holding a Master’s degree and have at least 3 years’ experience in acupuncture practice. The treatment methods of electroacupuncture and acupoints are shown in Table. 2.
Table. 2. Treatment methods of electroacupuncture and acupoints
The electroacupuncture group:
Preoperative electroacupuncture treatment and acupoint justification
The operation preparation begins 1 day before the operation, participants will be asked to fast from 8 hours before the operation. Participants will receive the 1st electroacupuncture treatment within 2 hours prior to the surgery.
We will perform the electroacupuncture procedure following the Guidance of Clinical Practice of Acupuncture[16]. Participants will be placed in the supine position at a separate space and asked to wear an eye-mask to prevent the patient from watching the treatment procedure. The researcher will sterilize the patient’s skin with 75% alcohol wipes before the treatment. Each acupuncture needle will be standard stainless steel, sterile, and disposable (0.25 × 40 mm and 0.30×40mm in length; Jia Jian, China). All patients will receive treatment at 17 standard acupuncture points: bilateral Hegu (LI4), Neiguan (PC6), Shenmen (HT7), Yingxiang (LI20), Zusanli (ST36), Shangxing (GV23) in all sessions. In addition, Baihui (GV20), Yintang (GV29), Anmian (EX-HN22) and Sanyinjiao (SP6) will be used in postoperative electroacupuncture treatment. All acupoints were selected according to the textbook, literature and clinical experience. The acupoints which we have selected will be located with reference to the acupuncture textbook of the International Standard Library of Chinese Medicine written by Zhang, Zhao, and Lao[17]. First the researcher will manipulate manually until the patient reports needling sensations (Deqi sensation). An electric stimulator (HANS-200B) will be connected to 3 pairs of needles: LI4-ST36 (bilaterally), GV20-GV23, using continuous wave type, low-frequency, 2-HZ and an intensity of 2 mA. Each treatment session will last for 30 min. After the removal of needles, the researcher will use a clean cotton wool to prevent bleeding by compressing the points. In the first treatment, 11 acupoints will be used and 17 acupoints will be used in the postoperative treatment. The acupoint selection and rationale are summarized in Table. 3.
Table. 3: The acupoint selection and rationale based on Traditional Chinese Medicine (TCM).
Preoperative electroacupuncture treatment and acupoint justification
Participants will be transferred to the ward within 30 min after the operation. They will receive the electroacupuncture treatment immediately upon arrival in the ward. Then, the participants will receive electroacupuncture treatment every 24 hours after the operation over the following 3 days. The electroacupuncture treatment will be the same as the preoperative electroacupuncture treatment described above, except that we will add the following 6 points: Baihui (GV20), Yintang (GV29), Anmian (EX-HN22) and Sanyinjiao (SP6).
The control group:
In the control group, Streitberger Placebo needle, a sham acupuncture device that has been widely reported and validated will be used[18]. The non-invasive sham needles will be performed 1.5 cun lateral and posterior to the true acupoints[19, 20]. The blunt tip of the sham needles will touch the surface of the skin but no penetration. The electric stimulator (HANS-200B) will be set beside the patients and 3 pairs of electrodes will be connected to the LI4-ST36 (bilaterally), GV20-GV23 for 30 minutes but no electrical current will be delivered.
Outcome measures
The participant’s recovery will be monitored during and after the operation. The primary outcome will be to assess participants’ postoperative pain scores by Numerical Rating Scale (NRS) hourly for 6 hours after surgery, then daily for 3 days after the operation. The secondary outcomes include the following: Heart Rate (HR) and Blood Pressure (BP) after operation, the sleep quality during the hospital stay (Actigragh), Quality of Recovery-15 (QoR-15) and MOS item short form health survey (SF-36). If the participants are unable to be managed according to the protocol for any reason including side effects, no further data will be collected. The assessment schedule is detailed in Table 1.
Primary outcome
Numerical Rating Scale (NRS):
NRS is a commonly used scale for assessing clinical pain. It is easier for patients to grade pain intensity with numbers rather than other measurements like the Visual Analog Scale. The NRS is a 0-10 points scale for pain, 0 indicating no pain and 10 indicating worst possible pain. NRS pain scores will be assessed hourly for 6 hours after surgery, then daily for 3 days[21, 22].
Secondary outcomes:
Heart Rate (HR) and Blood Pressure (BP):
The HR and BP will be monitored during and after the operation, which has been extensively utilized and validated to assess the patients’ vital signs. HR and BP will be assessed hourly for 6 hours after surgery, then daily for 3 days.
Actigraphy assessments:
The actigraphy is a wrist watch which can monitor patients’ sleep quality when worn on the wrist overnight. The main sleep indexes are sleep efficiency (SE), total sleep time (TST) and sleep awakenings (SA). The analysis of sleep condition and sleep quality will be performed by the software ActiLife6 (Version 6.8.1, Actigraph LLC) [23]. The Actigraphy assessment will be assessed 5 times: the night before the operation, the night of operation day and three night after operation until discharge.
Quality of Recovery-15(QoR-15):
The QoR-15 is a valid, extensive and efficient evaluation of patient’s postoperative recovery. The QoR-15 scale measures patients’ recovery from 5 aspects: pain, physical comfort, physical independence, psychological support, emotional state. The questionnaire consists of 15 items, with a score of 0 to 10, 0 representing no presence, 10 representing always present. The sum of the scores is the patient's QoR-15 score[24]. QoR-15 will be assessed 2 times which are: after surgery and day of discharge.
The MOS item short from health survey (SF-36):
The SF-36 consists of 36 items which are summated into 8 multiitem scales: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH) and 1 single-item scale on health transition. Higher scores represent better health status[25]. SF-36 will be assessed 2 times which are: after surgery and day of discharge.
Safety assessment:
Reasons for drop out
When a participant drops out before completing the study, the reasons for drop out will be recorded. We will terminate the treatment if there are serious adverse effects.
Adverse events
Participants will be informed the potential adverse events related to acupuncture procedure such as bruises, hematomas, infection, pain, during the signing of inform consent. Adverse events will be graded into: grade 1, mild, grade 2, moderate, grade 3, severe or medically significant. Any adverse events that occur during the trial will be recorded by the patients and doctors. Vital signs will be assessed at the time of the event, including Heart Rate, blood pressure and respiratory rate. All details of adverse events will be reported in the Case Report Form. If any severe adverse event (SAE) occurs, the Clinical Research Center of Drugs of the Shanghai University of Traditional Chinese Medicine will discover the blind, reveal the code of this participant in order to determine the correlation of the SAE with the intervention, and make the final decision as to whether to continue the study or not. We will analyze the influence of all events at the end of the trial.
Credibility of Treatment Rating Scale (CTRS) :
We will use the Credibility of Treatment Rating Scale (CTRS) to assessed the credibility of the acupuncture treatments[26, 27]. It consists 4 items and is used to assess the participants’ “perceived logic of the treatment,” “confidence in recommending the treatment to their friends who have similar complaints, “confidence in the treatment to alleviate their complaint,” and “likelihood that the treatment would alleviate their other complaints.”
Blinding success assessment:
After the final treatment is completed, we will test the success of blinding by asking the participants the following question “When you volunteered for the study, you were informed that you had equal odds of receiving traditional electroacupuncture or electroacupuncture-like simulation treatment. Our study is complete, which electroacupuncture do you think you received?” 3 choices will be provided for participants: electroacupuncture treatment group, electroacupuncture-like simulation treatment group and uncertain. If participants do not chose uncertain, we will ask the reason why they have made that assumption[28].
Monitoring:
To ensure the quality of this trial, the whole process will be conducted under the supervision of a qualified clinical trial expert and be carried out by Shanghai Municipal Hospital of Traditional Chinese Medicine. The Clinical Research Center of Drugs of the Shanghai University of Traditional Chinese Medicine will provide data monitoring with access to any interim results. It also identifies problems in the project, if any; the center makes the decisions to change the details of this protocol and announce the persons conducting the trial by written notice after approval by the application ethics committee. In addition, a qualified clinical trial expert will be invited to monitor this study and the PI will take full responsibility and will make the final decision.
Data management:
ResMan research Manager of the Clinical Trial Management Public Platform will be used to manage the original data, and the original data will be collected by blinded assessors and double-entered. The system will be tested and the relevant users will be trained before it is officially launched. Only the relevant personnel will receive the account number and password. The original data will be entered within 1 week of the participants finishing the all of the treatments. If the data is found to be uncertain, the data supervisor will notify the researcher to respond with a data question form. If necessary, the statistician will send a data question form to the researcher and the researcher's answer should be filled in the form. The question form is returned to the statistician by the inspector. The clinical supervisor will monitor the work of the clinical trial center at least once a month.
Statistical analysis:
An independent statistician blinded to group allocation will perform statistical analysis and the Intention- to-Treat (ITT) analysis. All data will be carried out by statistical software SPSS 23.0 for Windows, including the data from any participants who have dropped out of the trial. We will use multiple imputation to address any missing data. All demographic and clinical characteristics of the subjects (such as sex, age, and weight) will be processed based on descriptive analyses. We will identify the homogeneity of demographic characteristics and study variables between two groups. Quantitative data will be done as mean ± standard deviation for continuous variables while the qualitative data will be presented as the frequency and percentage. To analyze the primary outcome, area-under-the-curve (AUC) of the NRS pain scores will be calculated by plotting on the timescale using the trapezoidal method, and comparisons between groups will be made using the Student’s t test. For the secondary outcomes, blood pressure (BP), Heart Rate (HR), QoR-15, SF-36 and Actigraphy assessments (TST, SA and SE) between the 2 groups will be compared with Student’s t test or the Wilcoxon rank-sum test. All reported P values will be 2-sided, and a P value of less than 0.05 is considered statistically significant.