Effects of Perioperative Transauricular Vagus Nerve Electrical Stimulation on POD, POCD and CPSP

Study Overview
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Brief Summary
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Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) occur in 11-51% of patients after surgery, and its prevalence increases with age. The occurrence of delirium is associated with increased morbidity and mortality, prolonged hospital stay, worse functional recovery. Orthopedic procedures and specifically joint replacements have been considered as a major risk for development of chronic postsurgical pain (CPSP). Approximately 13-44% of patients will develop CPSP after knee or hip arthOpioid abuseroplasty. CPSP may cause the discomfort, distress, disability and opioid abuse. Mounting evidence has revealed that inflammation triggered by surgical trauma plays a key role in POD, POCD and CPSP. Recent studies found that vagus nerve stimulation showed the suppression of inflammation. In this study, the effect of perioperative transauricular vagus nerve stimulation on the prognosis of patients undergoing arthroplasty will be investigated, providing potential solutions for the prevention and treatment of postoperative cognitive dysfunction, postoperative delirium and chronic postsurgical pain.

Detailed Description
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The investigators assessed POD by the Confusion Assessment Method for the ICU twice daily for 7 days after surgery. Participants' cognitive function was assessed with neuropsychological battery tests. The tests included digit span (forward and backward), Corsi block, paired associate verbal learning, digit symbol test, trail-making test and so on.The investigators make a CPSP diagnosis based on the 11th revision of the International Classification of Diseases.

Official Title
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Effects of Perioperative Transauricular Vagus Nerve Electrical Stimulation on Postoperative Delirium, Postoperative Cognitive Dysfunction and Chronic Postsurgical Pain in Patients Undergoing Arthroplasty.

Conditions
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Postoperative Cognitive Dysfunction, Postoperative Delirium, Chronic Post Operative Pain

Intervention / Treatment
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* Device: transaricular vagus nerve stimulation
* Device: fake transaricular vagus nerve stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 50 to 80 years old. ASA grade I-Ⅲ. elective knee or hip replacement. Exclusion Criteria: Mini-Mental State Examination (MMSE) score < 23. Education years<7. Peptic ulcer disease, serious cardiac-cerebral vascular disease. Neurological or psychiatric disorders. History of drug and alcohol abuse. Hepatic and/or kidney dysfunction. BMI>35. Patients on antidepressants. ASA >Ⅲ.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>The transaricular vagus nerve stimulator was placed in the left ear trunk, which is dominated only by the auricular branch of the vagus nerve. Continuous stimulation was performed at a frequency of 25Hz with pulse width of 300 μs. The stimulation was adjusted to be higher than the perception threshold and lower than the pain threshold. Each stimulation lasted for 30 minutes, three times per day (morning, noon, evening), from 1 day before surgery to 7 days after surgery, and the treatment lasted for 9 consecutive days. | Device: transaricular vagus nerve stimulation<br>* The transaricular vagus nerve stimulator was placed in the left ear trunk, which is dominated only by the auricular branch of the vagus nerve. Continuous stimulation was performed at a frequency of 25Hz with pulse width of 300 μs. The stimulation was adjusted to be higher than the perception threshold and lower than the pain threshold. Each stimulation lasted for 30 minutes, three times per day (morning, noon, evening), from 1 day before surgery to 7 days after surgery, and the treatment lasted for 9 consecutive days.<br>|
| Sham Comparator: Control group<br>The transaricular vagus nerve stimulator was placed in the same position as the experimental group, covered with an insulating film and placed at the site of the stimulation, so that the patient could not actually receive the electrical stimulation. Continuous stimulation was performed at a frequency of 25Hz and pulse width of 300 μs, and the stimulation was adjusted to be higher than the perception threshold and lower than the pain threshold. Each stimulation lasted for 30 minutes, three times per day (morning, noon, evening), from 1 day before surgery to 7 days after surgery, for 9 consecutive days. | Device: fake transaricular vagus nerve stimulation<br>* The transaricular vagus nerve stimulator was placed in the same position as the experimental group, covered with an insulating film and placed at the site of the stimulation, so that the patient could not actually receive the electrical stimulation. Continuous stimulation was performed at a frequency of 25Hz and pulse width of 300 μs, and the stimulation was adjusted to be higher than the perception threshold and lower than the pain threshold. Each stimulation lasted for 30 minutes, three times per day (morning, noon, evening), from 1 day before surgery to 7 days after surgery, for 9 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative cognitive function | The incidence of POCD was compared between the experimental group and the control group.The preoperative and postoperative differences of the following scales were calculated and compared: Digit Span (forward and backward), Visual Retention and Paired Associate Verbal Learning subtests of the Wechsler Memory Scale, Digit Symbol subtest of the Wechsler Adult Intelligence ScaleRevised, Halstead-Reitan Trail Making Test (Part A), Corsi Block Test and Grooved Pegboard Test (favored and unfavored hand). The standard deviation (SD) for each test was computed from the preoperative scores. A participant whose postoperative performance declined by ≥1 SD as compared to each preoperative test score on ≥2 tests was classified as POCD. | 1 month after the surgery. | 
| Postoperative cognitive function | The incidence of POCD was compared between the experimental group and the control group.The preoperative and postoperative differences of the following scales were calculated and compared: Digit Span (forward and backward), Visual Retention and Paired Associate Verbal Learning subtests of the Wechsler Memory Scale, Digit Symbol subtest of the Wechsler Adult Intelligence ScaleRevised, Halstead-Reitan Trail Making Test (Part A), Corsi Block Test and Grooved Pegboard Test (favored and unfavored hand). The standard deviation (SD) for each test was computed from the preoperative scores. A participant whose postoperative performance declined by ≥1 SD as compared to each preoperative test score on ≥2 tests was classified as POCD. | 3 months after the surgery. | 
| Postoperative delirium | The incidence of POD was compared between the experimental group and the control group.Postoperative delirium was assessed by the Delirium Assessment Scale (CAM-ICU) | Consecutive 7 days after the surgery | 
| Acute postoperative pain | The incidence of acute postoperative pain was compared between the experimental group and the control group.Acute postoperative pain was assessed by Visual Analogue Scale(VAS) for 7 consecutive days within 1 week after surgery. | Consecutive 7 days after the surgery for acute pain | 
| Chronic Postsurgical pain | The incidence of chronic postoperative pain (CPSP) was assessed by the Short Form McGill Pain Questionnaire (SF-MPQ) and Neuropathic Pain Scale (NPS).The incidence of CPSP was compared between the experimental group and the control group. | 3 months after the surgery for chronic pain | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TNF-α level in peripheral venous blood | The incidence of TNF-α level (pg/ml) in peripheral venous blood was compared between the experimental group and the control group | 1 day before the surgery, Postoperative day 1, 3, 5 | 
| IL-6 level in peripheral venous blood | The incidence of IL-6 level (pg/ml) in peripheral venous blood was compared between the experimental group and the control group | 1 day before the surgery, Postoperative day 1, 3, 5 | 
| IL-1β level in peripheral venous blood | The incidence of IL-1β level (pg/ml) in peripheral venous blood was compared between the experimental group and the control group | 1 day before the surgery, Postoperative day 1, 3, 5 | 
| cortisol level in peripheral venous blood | The incidence of cortisol level (μg/dL) in peripheral venous blood was compared between the experimental group and the control group | 1 day before the surgery, Postoperative day 1, 3, 5 |