|Year : 2016 | Volume
| Issue : 1 | Page : 17-24
Transcutaneous electrical acupoint stimulation with different acupoint combinations on opioid consumption in patients undergoing off-pump coronary artery bypass grafting: study protocol for a randomized double-blind controlled trial
Hui Zhang1, Chong Lei1, Tao-yuan Zhang1, Li-hong Hou1, Qiang Wang1, Hai-long Dong1, Jian-ge Han2, Li-ze Xiong1
1 Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi Province, China
2 Department of Anesthesiology, Tianjin Chest Hospital, Tianjin, China
|Date of Web Publication||5-Apr-2016|
Department of Anesthesiology, Tianjin Chest Hospital, Tianjin
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi Province
Source of Support: None, Conflict of Interest: None
Background: The demand for improved anesthesia during off-pump coronary artery bypass grafting (OP-CABG) is continually increasing. Ensuring stable hemodynamics and balanced myocardial oxygen supply during OP-CABG are key issues that remain to be resolved. There is evidence that acupuncture anesthesia can decrease mortality after OP-CABG, while reducing the dose of anesthesia required, minimizing surgical complications, and decreasing medical costs. Acupuncture at distal-proximal acupoints in combination is the most commonly used method requiring acupoint compatibility. We hypothesize that electroacupuncture at distal-proximal and regional acupoints prior to OP-CABG will reduce the dosage of anesthesia required during OP-CABG, and minimize postoperative complications.
Methods/Design: This prospective, randomized, double-blind, controlled trial will be performed at the Departments of Anesthesiology at Xijing Hospital, Fourth Military Medical University, and Tianjin Chest Hospital, China. A total of 186 patients scheduled for OP-CABG in these two hospitals will be included in the study. The patients will be divided into three groups: distal-proximal acupoints group (acupuncture at the Danzhong (CV17) and Hegu (LI4) acupoints); regional acupoints group (acupuncture at the Danzhong (CV17) and Juque (CV14) acupoints); and non-acupoint group (acupuncture at a site 2 cm lateral from the Danzhong (CV17) and Juque (CV14) acupoints). All interventions will start 30 minutes prior to anesthesia and continue until the beginning of anesthesia. The primary outcome is the dose of sufentanil used for anesthesia. Secondary outcomes are cardiac troponin I content, inotropic score, dose of propofol used for anesthesia, duration of mechanical ventilation, duration of stay in the intensive care unit, length of postoperative hospital stay, incidence of overall complications within 30 days of surgery, and incidence of overall mortality within 30 days of surgery. Adverse events will be also evaluated.
Discussion: This trial protocol will determine whether acupuncture at distal-proximal or regional acupoints can reduce anesthetic dose and postoperative complications in OP-CABG surgery, with the purpose of ensuring patient safety in the perioperative phase.
Trial registration: ClinicalTrals.gov identifier: NCT02443220; registered on 18 August 2014.
Ethical approval: The protocol was approved by the Ethics Committee on Clinical Trials of Drugs, Xijing Hospital, and the Ethics Committee on Clinical Trials, Tianjin Chest Hospital, China. Written informed consent regarding trial procedure and treatment protocol will be obtained from each subject.
Keywords: clinical trial; acupuncture; anesthesia; electroacupuncture; off-pump coronary artery bypass grafting; intraoperative anesthesia; sufentanil; perioperative phase; regional acupoints; distal-proximal acupoint; complication; adverse events
|How to cite this article:|
Zhang H, Lei C, Zhang Ty, Hou Lh, Wang Q, Dong Hl, Han Jg, Xiong Lz. Transcutaneous electrical acupoint stimulation with different acupoint combinations on opioid consumption in patients undergoing off-pump coronary artery bypass grafting: study protocol for a randomized double-blind controlled trial. Clin Trials Degener Dis 2016;1:17-24
|How to cite this URL:|
Zhang H, Lei C, Zhang Ty, Hou Lh, Wang Q, Dong Hl, Han Jg, Xiong Lz. Transcutaneous electrical acupoint stimulation with different acupoint combinations on opioid consumption in patients undergoing off-pump coronary artery bypass grafting: study protocol for a randomized double-blind controlled trial. Clin Trials Degener Dis [serial online] 2016 [cited 2020 Jul 9];1:17-24. Available from: http://www.clinicaltdd.com/text.asp?2016/1/1/17/179743
Hui Zhang, Chong Lei.
These authors contributed equally to this paper.
Conflicts of interest
LZX, JGH, HLD, QW, and HLD conceived and designed the trial protocol. HZ, CL, TYZ and LHH performed experiments. HZ and CL were responsible for writing and revision of the paper. All authors approved the final version of this paper.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
| Background|| |
Mounting evidence demonstrates that electroacupuncture has multiple clinical effects: Hou et al. (2013) found that electroacupuncture at Taichong (LR3) and Zusanli (ST36) promotes venous return in the lower extremities of older patients with malignant tumors of the gastrointestinal tract after surgery; at Yanglingquan (SP9) and Sanyinjiao (SP6), electroacupuncture decreases blood viscosity, promotes blood circulation, and activates anticoagulation mechanisms. In addition, our previous studies have shown that acupuncture has a strong cardioprotective effect (Yang et al., 2010; Ni et al., 2012). Electroacupuncture also regulates immune function (Garbo et al., 2013), reduces allergic reactions and alleviates postoperative pains (Zhang et al., 2013), as well as protecting against ischemia/reperfusion injury in animals and humans (Xiong et al., 2010; Wang et al., 2012). Results from our previous experiments investigating the effect of acupuncture pretreatment in cerebral ischemia are summarized in [Table 1]. The benefits of acupuncture at acupoints are likely to be related to the endocannabinoid, endogenous opioid peptide, and anti-oxidative stress systems (Wang et al., 2009, 2011).
|Table 1: Summary of literature from our group on pretreatment with acupuncture anesthesia |
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Many factors influence the curative effects of acupuncture, including acupuncture technique used, and acupoint specificity. Furthermore, the compatibility of acupoints is a key influential factor in the effects of acupuncture. However, because acupuncture is performed by clinical physicians according to their experience but without unified standards or guidelines, this results in a range of clinical effects. Acupuncture at a single acupoint can have clinical curative effects, but 72.34% of current clinical studies use acupoint compatibility. In studies involving two-acupoint compatibility acupuncture, various rules can be followed, such as compatibility according to regions, meridians or disease symptoms. Region-based acupoint acupuncture is the most basic and commonly used method. It involves four domains of acupoint compatibility: distal-proximal, upper-lower, anterior-posterior, and left-right. Distal-proximal acupoint, acupuncture is a widely-used technique in which acupoints are selected in regions distant from and near to the lesion. We previously studied acupoint compatibility rules in the treatment of headache; these rules can be grouped into three types, based on symptoms, acupoint region, or time. Symptom-based and region-based acupoint compatibility rules are those most widely followed, suggesting that they should be considered first.
Acupuncture anesthesia refers to a method of anesthesia in which acupuncture or electroacupuncture are performed according to the site of surgery and type of disease, as per meridian-based, symptom-based or regional acupoint rules (Xu et al., 2013; Min et al., 2015). This method has the advantages of safe use, few physiological interventions, rapid postoperative recovery, few complications, and unsatisfactory muscle relaxation. A recent clinical study has demonstrated that acupuncture anesthesia can decrease morbidity and reduce medical costs in patients undergoing open heart surgery under cardiopulmonary bypass (Zhou et al., 2011). In addition, our previous findings show that use of acupuncture anesthesia during sinusotomy can markedly reduce both analgesic drug dosage and surgical complications (Wang et al., 2014).
Off-pump coronary artery bypass grafting (OP-CABG) has recently become a popular treatment for coronary heart disease and is more suitable for older patients with organ function impairment than other methods (Lamy et al., 2013). Compared with on-pump CABG, OP-CABG avoids cardiopulmonary bypass and subsequent general inflammatory reaction, and is associated with lower morbidity and fewer complications, in particular in highly vulnerable heart disease patients. With the gradual development of the technique and continual improvement of surgical instruments, OP-CABG is becoming increasingly suitable for high-risk patients. However, because OP-CABG is performed without mechanical assistance, anesthesia management is difficult, and close control of anesthetic dose is especially important during this procedure. Ensuring stable hemodynamics and myocardial oxygenation during OP-CABG is an issue that remains to be resolved.
Although a large number of animal and clinical studies have demonstrated the multiple effects of acupuncture anesthesia, the advantages and disadvantages of distal-proximal and regional acupoint compatibility and related issues remain under debate, and few studies have investigated them systematically. The aim of the present trial protocol is to determine whether electroacupuncture at the distal-proximal or regional acupoints can effectively reduce anesthetic dosage during OP-CABG while limiting postoperative complications, with the purpose of ensuring the safety of patients undergoing OP-CABG.
| Methods/Design|| |
A prospective, randomized, double-blind, controlled trial ([Figure 1]).
|Figure 1: Flowchart of trial protocol. |
OP-CABG: Off-pump coronary artery bypass grafting.
Click here to view
We will recruit 186 patients scheduled to undergo OP-CABG in the Departments of Anesthesiology at Xijing Hospital, Fourth Military Medical University, and Tianjin Chest Hospital, China, through outpatient visits. All recruited patients should meet the following criteria:
- New York Heart Association (NYHA) class I-III
- Scheduled for OP-CABG
- First thoracotomy
- Signed informed consent form
- Undergoing surgery within 12 hours of admission to hospital
- Severe complications or life expectancy < 1 year at the time of enrollment
- Hemodynamic instability, as defined by systolic blood pressure < 90 mmHg (1 mmHg = 0.133 kPa)
- Preoperative intra-aortic balloon pump or ventricular assisted device
- Severe hepatic or renal dysfunction
- Exchange to cardiopulmonary bypass during surgery
- Mediastinal fiber thickening or severe pleural adhesions
- Severe systemic infection
- Contraindications to the use of electroacupuncture, such as skin damage or infection at acupoints
- Suffering from nervous system disease or abnormal mental state
- Participating in another clinical trial < 3 months prior to enrollment
- On request of the patients
- Severe adverse events, complications that are related to the trial
- Safety reasons determined by the trial admission or the advisory board
- If the physican comes to the conclusion that continuing the trial is harmful to the patient's well-being
Blinding and interventions
Patients, anesthesiologists, index recorders and data analyzers will be blinded to grouping. The trial designers LZX, HLD, JGH and QW will arrange and control the whole trial process. A sealed envelope containing computer-generated randomized information will be prepared, taking care to avoid unbalanced grouping with respect to age, sex, NYHA class or surgeon. When all included patients have been randomized, the envelopes will be opened and each patient will be allocated a random number.
Patients may or may not feel a sensation when undergoing transcutaneous electroacupuncture; the patients will be informed of this prior to surgery. The 186 patients will be randomly and equally divided into three groups using a 1:1:1 matching method: (1) Distal-proximal acupoints group: acupuncture at the Danzhong acupoint (CV17; located on the anterior midline, at the level of the 4 th intercostal space) and bilateral Hegu acupoints (LI4; located on the dorsum of the hand, between the 1 st and 2 nd metacarpal bones, approximately in the middle of the 2 nd metacarpal on the radial side); (2) regional acupoints group: acupuncture at Danzhong (CV17) and Juque (CV14; located on the midline of the abdomen, 6 cun (1 cun = the width of the interphalangeal joint of the patient's thumb) above the umbilicus); (3) non-acupoint group: acupuncture at a site 2 cm lateral from Danzhong (CV17) and Juque (CV14). Transcutaneous electroacupuncture apparatus (SDZ-V, Suzhou Medical Appliance Company, China) will be used. The disperse-dense wave will have a frequency of 2/10 Hz, and current intensity will be 7-11 mA. The final stimulus current will be defined as the intensity at which the patient can tolerate the maximal needling sensation (de qi). After 30 minutes of transcutaneous electroacupuncture, OP-CABG will be carried out.
All operations will be performed by a group of professional surgeons, under tracheal intubation and general anesthesia. For general anesthesia, midazolam (0.03 mg/kg), propofol (target plasma concentration of 2.0 μg/mL) and sufentanil (target effect-site concentration of 0.2 ng/mL, which will be increased by 0.1 ng/mL/min) will be administered by target-controlled infusion. When patients lose consciousness, rocuronium bromide (0.6 mg/kg) will be given and tracheal intubation will be performed at a bispectral index (BIS) of 40-60.
Blood gas analysis is necessary during the surgery and a person will be designated to place a floating catheter and record data. When hemoglobin is lower than 80 g/L, blood products will be given according to blood loss. At the end of surgery, the propofol and sufentanil infusions will be terminated and patients will be transferred to the intensive care unit (ICU).
For hemodynamics maintenance, bolus intravenous infusion of nitroglycerin (0.2 μg/kg/min) should be given during surgery to expand the coronary artery. When the ascending aorta is blocked or blood pressure is > 140 mmHg (1 mmHg = 0.133 kPa), nitroglycerin dose should be increased to 1-3 μg/kg/min to decrease blood pressure. During the period of anesthesia induction, once blood pressure is decreased, 5-10 μg norepinephrine will be administered intravenously and intermittently. If heart rate and blood pressure greatly decrease and the vasoactive agent is not effective, administration of anesthetic (propofol and sufentanil) should be terminated, and will resume when hemodynamics recover to normal level. When the bridged anterior descending branch is revascularized, a bolus intravenous injection of 0.03-1.00 μg/kg/min epinephrine will be given if necessary.
The total dose of sufentanil used during anesthesia induction and maintenance and the target effect-site concentration of sufentanil at different time points during anesthesia (T0: the onset of anesthesia (baseline); T1: at the time of loss of consciousness; T2: at the time before intubation; T3: 1 minute after intubation; T4: at the start of surgery; T5: after the sternotomy; T6: after the separation of internal mammary artery; T7: before clamping the aorta; T8: at the time of releasing lateral forceps; T9: 5 minutes after revascularization; T10: at the time of closure; T11; at the end of surgery).
- Degree of myocardial injury: cardiac troponin I (cTn I) content at 6, 12, 24, 48 and 72 hours postoperatively and inotrope score at 1, 6, 12, 24, 48 and 72 hours postoperatively. Inotropic score is calculated as the doses of dopamine (×1) + dobutamine (×1) + amrinone (×1) + milrinone (×10) + epinephrine (×100) + norepinephrine (×100) + isoprenaline (×100).
- Perioperative anesthesia monitoring index: systolic pressure, diastolic pressure, mean arterial pressure, central venous pressure, heart rate, BIS value at T0 (baseline)-T11 and floating catheter data at T4-T11.
- Postoperative mechanical ventilation time: time period from the end of surgery to removal of the endotracheal tube
- Length of ICU stay
- Length of postoperative hospital stay
- Incidence of overall complications within 30 days of surgery
- Overall mortality within 30 days of surgery: cardiac and non-cardiac mortality
- The timing of outcome evaluation is shown in [Table 2].
Evaluation criteria for adverse events
Researchers should faithfully record adverse events including onset time, severity, duration, management measures, and degree of improvement. The criteria used to assess the severity of adverse events should be indicated. The relationship between adverse events and intervention drugs is to be described using five classification criteria: certainly related, likely related, likely unrelated, unrelated and cannot be evaluated. All adverse events should be followed up until fully resolved or stabilized.
Types of adverse events
Blood system complications including anemia; respiratory system complications including pneumonia, respiratory failure, pulmonary embolism, pulmonary atelectasis, and pleural effusion; cardiovascular complications including angina pectoris, heart failure, and arrhythmia; gastrointestinal complications including hepatic impairment, and digestive tract hemorrhage or perforation; nervous system complications including delirium and stroke; urinary system complications including urinary system infection and acute renal impairment; and other complications including infection, septicemia, and deep vein thrombosis.
Possible adverse events and observation methods
Most patients have good tolerance to transcutaneous electrical acupoint stimulation and experience mild adverse reactions that disappear after stopping stimulation. No adverse reactions were observed in preliminary experiments. No severe adverse reaction has been reported during studies on transcutaneous stimulation.
Severe adverse events
Severe adverse events are defined as those that lead to one of the following consequences: death, life-threatening reaction, prolonged hospital stay, disability or permanent damage, or birth defects. Any adverse event occurring during the trial should be reported to the responsible researchers from the Department of Anesthesiology and the Ethics Committee for Clinical Drug Trials of Xijing Hospital within 24 hours of occurrence.
The data safety management committee will be composed of surgeons, ICU physicians and anesthesiologists. When half of the patients scheduled to undergo OP-CABG have been included, an interim analysis will be performed by the committee. If mortality is significantly greater in any test group than in the control group, or there are more complications, the trial should be terminated.
Ethical considerations and informed consent
The sponsors of the trial should give the protocol and signed informed consent forms to the independent Ethics Committee for Clinical Drug Trials for approval. The trial will not be performed until approval has been acquired. Prior to trial, informed consent should be obtained from each patient. The researchers should explain the nature, objective and risk of the trial to each patient and let them know he/she can withdraw from the trial at any time after enrollment. The patients' participation should be voluntary, and the informed consent form should be signed and dated by both the patients and the researchers.
Two researchers will transcribe the trial information independently, from electronic medical records into a table prepared by a researcher responsible for randomized grouping. The transcribed documents will be dated and saved in a designated computer. When all patients are included and followed up, two copies of the documents will be rechecked and a password will be set by the researchers in charge. All data relating to this trial will be preserved by the Departments of Anesthesiology at Xijing Hospital and Tianjin Chest Hospital. The three patient groups will be designated Groups A, B and C, and all data will be fully disclosed to the Department of Biostatisticsfor statistical analysis, who will create a report. The researchers in charge will then create a final report collating all related data including the biostatistics report.
Management of loss of cases
All patients eligible for participation can withdraw from the trial at any time, for any reason. Lost cases are defined by those who do not complete the designated observation period. The possible reasons for loss will be listed in the case report form by the researchers and will generally fall into six categories: adverse events, lack of efficacy, departure from trial protocol (including noncompliance), lost to follow up (including self-withdrawal from the trial), termination by sponsors, and others. Researchers should contact the lost patients as far as possible to have a near-complete evaluation and make a final conclusion. Patients lost because of adverse reaction as confirmed by follow up observation should be recorded in the case report form and reported to the sponsors of the trial.
Sample size calculation
Preliminary experimental findings showed that sufentanil maintains the hemodynamic change required for OP-CABG at a blood drug level of 351 ± 88 μg. PASS 14.0 software will be used to calculate sample size. It is hypothesized that the dosage of sufentanil used in the regional acupoints group is decreased by 5% and in the distal-proximal acupoints group by 15%, when β ≤ 0.1, power = 90%, and significance level (bilateral) α = 0.05, sample size per group is calculated as n = 52. If the loss rate is 15%, then n = 62 patients will be required in each group.
SPSS 19.0 software (SPSS, Chicago, IL, USA) will be used for statistical analysis. Normally-distributed measurement data will be expressed as the mean, SD, minimal and maximal, and non-normally distributed data as lower quartile (Q1), median and upper quartile (Q3). Numeration data will be expressed as the constituent ratio.
Fisher's exact test will be used for comparison of numeration data among groups. One-way analysis of variance will be used for comparison of normally distributed measurement data (mean, SD) among groups and Tamhane's T2 test for comparison of non-normally distributed measurement data between groups. The Kruskal-Wallis rank sum test will be used for comparison of non-normally distributed numeration data (Q1, median and Q3) between groups.
Repeated measures analysis of variance will be used for between-group comparisons of total sufentanil dose, cTn I content and inotrope score at different postoperative times. The Kruskal-Wallis rank sum test will be used for comparisons of perioperative anesthesia indices, postoperative mechanical ventilation time, ICU stay and hospital days among groups. McNemar's chi-square test will be used for between-group comparisons of incidence of overall complications and overall mortality within 30 days postoperatively. The alpha level was set at 0.05.
| Discussion|| |
This trial protocol is based strictly on the principle of a randomized controlled trial. The dosage of analgesic (sufentanil) during the trial is the primary outcome that will be used to evaluate therapeutic effects.
Sufentanil provides strong analgesic effects while maintaining stable hemodynamics and ensuring sufficient myocardial oxygenation, which can be used to monitor anesthesia during surgery. Some safety indices will be also monitored and evaluated, namely perioperative anesthesia, postoperative mechanical ventilation time, ICU stay, hospital days, incidence of overall complications or mortality within 30 days of surgery, and adverse events.
This trial protocol will evaluate the overall anesthetic effects and safety during OP-CABG after transcutaneous electrical acupoint stimulation at distal-proximal and regional acupoints. It is powered to determine whether electroacupuncture performed at these acupoints can effectively reduce the anesthetic dose during OP-CABG, and minimize postoperative complications, with the purpose of ensuring the safety of patients undergoing OP-CABG.
Recruitment of participants at time of submission.
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[Table 1], [Table 2]