Transcutaneous Electrical Acupoint Stimulation Before Induction of Anesthesia Prevents Sufentanil- Induced Cough: A Prospective, Randomized, Controlled Study

Junjie Xie Wenzhou Medical University First A liated Hospital Yunchang Mo Wenzhou Medical University First A liated Hospital Junkai Wang Zhejiang Provincial People's Hospital Lili Yang Lishui Central Hospital and Fifth A liated Hospital of Wenzhou Medical College Haijuan He Taizhou Hospital of Zhejiang Province Junlu Wang (  wangjunlu973@163.com ) First a liated hospital of Wenzhou medical university


Introduction
Sufentanyl,an opioid analgesic drug,is widely used in clinical anesthesia due to its strong analgesic effect,rapid-onset,and stable cardiovascular effects.However,intravenous sufentanil injection can evoke cough,which increases risk during anesthesia.A previous report (1) showed that the incidence of sufentanil-induced cough is about 28% in Asian individuals.Although sufentanil-induced cough is transient and benign for the most time,it could cause serious consequences in cases with ocular trauma,pneumothorax,a reactive/di cult airway,artery dissection,or patients undergoing neurosurgery (2).Given the highly contgious nature of some pandemic,such as COVID-19,if the patient cough during the induction,tracheal intubation carries a high risk of transmission to the intubator.
TEAS has an analgesic effect,reduces the perioperative in ammatory response,and promotes immune function and oxygenation. TEAS has been proved to have a signi cant effect on the treatment of lung diseases, such as COPD, asthma, etc (8,9).But for the time being,no researchers have used TEAS to prevent sufentanil-induced cough.Therefore,we postulated that patients receive TEAS for 30 min before administration of sufentanil may suppress the undesirable cough.We here tested this hypothesis in a prospective,multicenter,double-blind,randomized, controlled clinical trial.

Materials And Methods
This study was conducted after approval from the ethics committee of the First A liated Hospital of Wenzhou Medical University(2016 − 142)(Wenzhou,China) and registered at the Chinese Clinical Trial Registry(ChiCTR-INR-16008759).Written informed consent was obtained from all patients.
We considered patients of either sex for inclusion if they were aged between 20 and 75 years,had an ASA physical status or ,and were undergoing elective surgical procedures under general anesthesia.
The exclusion criteria were as follows:any incision or surgical scar in an acupoint;infection in an acupoint;nerve injury in the upper or lower limbs;a history of spinal surgery;allergic reaction to drugs used in the test;sinus bradycardia;severe neurological disease(intracranial hypertension,cerebral hernia,cerebral tumor,cerebral aneurysm);severe respiratory disease(asthma,pneumothorax,chronic obstructive pulmonary disease,bronchial hyperresponsiveness);smoking;severe cardiovascular disease(myocardial infarction,aortic dissection);addiction to anaesthetic or recent history of opioid use;upper respiratory tract infection in the previous 2 weeks;biliary tract surgery;or treatment with angiotensin-converting-enzyme inhibitors(ACE-inhibitors).
This study was conducted from August 2016 to July 2019 at First A liated Hospital of Wenzhou Medical University.300 patients were randomly and equally divided into ve groups(n = 60):Patients did not receive TEAS in control group(C group);Patients received 2 Hz TEAS at the bilateral LI4/PC6 in 2A group;Patients received 100 Hz TEAS at the bilateral LI4/PC6 in 100A group;Patients received 2 Hz TEAS at the bilateral ST36/SP6 in 2B group;Patients received 100 Hz TEAS at the bilateral ST36/SP6 in 100B group.The locations of all the acupoints have been showed in Fig. 1.
Except for C group,other groups were received TEAS for 30 min before induction of anesthesia.Venous access was established using a 22G cannula on the dorsum of the non-dominant hand,before entering the operating room.No medication other than crystal liquid was given.Upon arrival in the operating room,non-invasive blood pressure,oxygen saturation,and electrocardiography were recorded.After commencing induction of anesthesia,sufentanil(0.5 µ/kg) was given within 2 s.An independent observer observed and recorded the occurrence of cough after sufentanil administration in 1 min.The severity of cough was graded as mild(1-2 coughs),moderate(3-5 coughs),and severe(> 5 coughs).After this observation nished,propofol(2 mg/kg) and rocuronium(1 mg/kg) were given and endotracheal intubation was achieved.MAP and HR before(T0) and 1 min after(T1) sufentanil injection were recorded.
In the time from sufentanil administration to successful endotracheal intubation,an oxygen mask was given if the blood saturation was < 90%;norepinephrine was given if the systolic blood pressure(SBP) was < 90 mmHg or the diastolic blood pressure(DBP) was < 60 mmHg;and atropine 0.5 mg was given if the HR was < 50/min.

Statistical analysis
The required sample size was estimated based on a 30% reported incidence of sufentanil-induced cough, and an assumption that TEAS would reduce the incidence of cough to 8%, according to a pilot study. With α = 0.05 and β = 0.20, a minimum of 60 patients per group were required.
We use a randomization table to randomize patients.The random numbers were divided by 5; the remainder of the division sum (0, 1, 2, 3, 4) was used to decide the allocation to each of the 5 groups.
All test data are expressed as mean ± standard deviation, and SPSS 20.0 software was used for statistical analyses. Demographic characteristics were compared using independent samples u-test. The cough incidence was compared using the chi-square test, and cough severity was compared using the Mann−Whitney U test or Kruskal−Wallis test. P < 0.05 was considered statistically signi cant.

Result
A total of 339 patients were recruited from August 2016 to July 2019, 39 unquali ed patients were removed,300 patients were enrolled nally(5 patients with history of asthma,19 patients were smoking,15 patients were taking ACE inhibitor) (Fig. 2).
The patient characteristics(age,weight,sex) in the 5 groups have no difference( Table 1). The incidence of sufentani-induced cough in C group,2A group,2Bgroup,100A group and 100B group were 37%,27%,27%,12% and 13%,respectively.Compared with C group,the incidence of 100A group and 100B group were signi cantly lower(P < 0.05)( Table 2). The severity of cough did not show statistical difference( Table 3).The MAP and HR between ve groups had no statistical difference( Table 4,Table 5).After the injection of sufentani,no patients showed a low blood oxygen saturation(SpO 2 < 90%),low blood pressure, apnea, nausea, vomiting, or any other adverse reactions. The Characteristics of patients did not differ signi cantly in the 5 groups (P > 0.05).  The severity of coughing was not signi cantly difference among the groups (P > 0.05). Table 4 The heart rate (HR) before (T0) and after (T1) sufentanil administration. Values are the mean (SD).

Discussion
Our study revealed that using TEAS at a frequency of 100 Hz for 30 min at the bilateral LI4/PC6 and ST36/SP6 acupoints before induction of general anesthesia can signi cantly reduce the incidence of sufentanil-induced cough.
Sufentanil is a new type of synthetic opioid drug that is widely applied for the rapid induction of anesthesia. However, i.v. injection of fentanyl can evoke coughing, which increases the risks associated with anesthesia. Li et al (10) has suggested that use of peripheral i.v. sufentanil 0.5 µg/kg during anesthesia induction was associated with a cough incidence of 37%.An et al (11) found that the incidence of sufentanil-induced cough could be 45.8% by using 1 µg/kg sufentanil.
Although the mechanism is unclear, it may involve the following (12,13). Opioid receptors are divided into µ, κ, δ, σ types, depending on their activation. It is possible that a particular type of opioid receptor present in the airway plays an important role in mediating the sufentanil-induced cough. Acute conditioning of rapidly adapting stretch receptors (RARS) and C-bers may play a role. In particular, the laryngeal and tracheal RARS in the bronchial tree, probably act as the primary sensory pathways of the cough re ex. C-bers can not only induce cough by releasing tachykinin, which activates RARS, but can also cause neurogenic in ammation, and inhibit the cough re ex through a central gating mechanism. Intravenous sufentanil may cause bronchial smooth muscle contraction, and activation of RARS in the adjacent regions may cause coughing. Airway high reactivity (AHR) is considered to play a role in sufentanil-induced coughing.
Electroacupuncture is widely used in the clinic as an analgesic (14) and as a means to achieve perioperative multiple organ function protection (15,16). Previous studies have suggested that the endogenous opioid peptides enkephalin, beta-endorphin, and dynorphin are involved in mediating the analgesic effect of electroacupuncture (17). Another previous study demonstrated that low and high frequency TEAS, given for 30 min, could increase the enkephalin and dynorphin levels in human lumbar CSF (18).
In our study,we found that patients received 100 Hz can effectively prevent sufentanil-induced cough,either LI4/PC6 or ST36/SP6.We hypothesized that the mechanism of this phenomenon is the increase dynorphin in CSF after TEAS.The production of endogenous opioid peptides is the basis of electroacupuncture analgesia. Abundant opioid receptors are located in the central nervous system (CNS), such as the head of the caudate nucleus, the nucleus accumbens, the amygdaloid nucleus, the periaqueductal gray, and the nucleus raphe magnus (19).With the change of electroacupuncture frequency,the opioid peptides produced will also change.Low frequency electroacupuncture produces enkephalin,while high frequency electroacupuncture produces dynorphin,either LI4/PC6 or ST36/SP6 (18,(20)(21).Opioids may inhibit cough re ex by acting directly on the cough center in the medulla, a highly selective κ-opioid receptor agonist has potent antitussive effects when administered either i.c.v. or i.p., and that µ2-rather than µ1-opioid receptors are involved in the µ-opioid receptor-induced antitussive affects (22,23).Therefore,We consider that the possible mechanism underlying this phenomenon is the 100 Hz TEAS-mediated release of dynorphin into the CSF, leading in part to κ-receptor activation, which could then have an antitussive effect,while the endorphins produced by 2 Hz TEAS could not selectively activate the µ2-receptor.
In addition, a previous study (24) found that sedation could inhibit sufentanil-induced cough; the sedative effect of TEAS may be one of the reasons for inhibition of sufentanil-induced cough by TEAS.
In recent years, there are more and more applications of electroacupuncture in the perioperative period. This study found a new role of electroacupuncture in the perioperative period, providing clinical evidence for the study of the mechanism of electroacupuncture.
The study had some limitations. Firstly, we could not use an antagonist in patients. Secondly, we only chose the number of coughs as the primary outcome, and did not investigate any other biochemical factors in our study. Thirdly, the size of the electrode slice we used was about 3.5 cm × 3.5 cm, which was too large to avoid affecting other acupoints; therefore, we did not set up a non-acupoint group. These limitations should be addressed in future research.

Availability of data and materials
Following the publication of the main trial results anonymous data sets will be available with agreement from Professor Junlu Wang,First a liated hospital of Wenzhou university,China.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by Wenzhou Municipal Science and Technology Bureau (award number:2018Y1122).The funding body had no role in the design of the study and collection,analysis and interpretation of data and in writing the manuscript.  Location of LI4/PC6 and ST36/SP36