Transcutaneous Auricular Vagus Nerve Stimulation for Preventing Emergence Agitation and Delirium After Pediatric Tonsillectomy and Adenoidectomy: A Randomized, Double-Blind, Interventional Study
Phase: NA
Conditions: Emergence Agitation, Emergence Delirium
Sponsor: The First Affiliated Hospital of Zhejiang Chinese Medical University

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Study Protocol 
Title 
Transcutaneous Auricular Vagus Nerve Stimulation for the Prevention of Emergence Agitation 
and Emergence Delirium After Adenotonsillectomy in Children: A Randomized, Double-Blind, 
Interventional Study 
 
Background 
Emergence agitation (EA) and emergence delirium (ED) refer to a cluster of negative 
behavioral symptoms occurring during the early recovery phase from general anesthesia in children, 
characterized by crying, restlessness, and disorientation. The reported incidence ranges from 25% 
to 80% 1-5.The occurrence of ED not only delays recovery, increases postoperative complications 
and healthcare costs, but also reduces parental satisfaction with anesthesia management 6,making it 
a pressing issue in pediatric anesthesia.  
Although the exact etiology of ED remains unclear,it is strongly associated with exposure to 
volatile anesthetics. Several studies have demonstrated that inhalational agents such as isoflurane, 
halothane, sevoflurane, and desflurane are linked to a higher incidence of EA/ED, with sevoflurane 
showing the strongest association and significantly increasing the risk of pediatric anesthesia 
emergence delirium (PAED). In addition to anesthetic factors, the type of surgery plays an important 
role. EA is less frequent after tonsillectomy, thyroid, or circumcision surgeries, but occurs more 
commonly following ophthalmic and otolaryngologic procedures 6.Moreover, preoperative anxiety 
and postoperative pain are closely related to ED. Higher preoperative anxiety scores on the modified 
Yale Preoperative Anxiety Scale (mYPAS) are independently associated with an increased risk of 
ED, with each 10-point increase correlating to a 10% rise in risk 7.Postoperative pain has also been 
recognized as a major trigger for ED. Therefore, reducing anxiety and optimizing perioperative 
analgesia may help decrease the incidence of ED following sevoflurane anesthesia3,8-10. 
To prevent or manage ED,various pharmacological and non-pharmacological strategies have 
been explored 11-13, but their overall efficacy remains uncertain. Agents such as fentanyl, propofol, 
and dexmedetomidine may alleviate symptoms but can prolong emergence or induce respiratory 
depression. Midazolam has been shown to reduce the incidence of ED in children 14. Intravenous 
administration is the most commonly used route for prevention15,and a single bolus of 0.5 mL/kg 
midazolam administered at the beginning or end of surgery has demonstrated efficacy 14. However, 
due to its relatively long half-life(0.79–2.83h) and active metabolite(1-hydroxymidazolam), its use 
may delay postoperative recovery 16,17. 
 

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Among non-pharmacological approaches, behavioral interventions such as handheld video 
games and video distraction can help relieve preoperative anxiety 18,19,but they are not suitable for 
anesthetized or unconscious children. Although parental presence during induction may reduce 
anxiety to some extent, this approach is often impractical in the operating room and may interfere 
with surgical workflow 19. 
Recently, growing evidence has emphasized the role of the autonomic nervous system (ANS) 
in postoperative recovery. Increased vagal activity has been shown to improve physical 
performance20, reduce postoperative pain scores 21-23, alleviate anxiety and depression 24and 
improve sleep quality 25. These effects are partly through the cholinergic anti-inflammatory pathway 
and related mechanisms 26-28.However, perioperative conditions such as systemic inflammation 29, 
regional anesthesia 30and general anesthesia 31 may impair autonomic regulation, leading to 
decreased vagal tone and sympathetic overactivation 20,32,33.  
Transcutaneous auricular vagus nerve stimulation (ta-VNS), a safe and non-invasive 
neuromodulatory technique, stimulates the auricular branch of the vagus nerve located in the cymba 
conchae 34, thereby activating vagal pathways to produce anti-inflammatory, analgesic, and 
anxiolytic effects while mitigating stress responses 21-23. It represents a promising strategy to 
modulate autonomic balance and improve perioperative outcomes.  
Based on these findings, we designed a randomized, double-blind, controlled trial to 
systematically evaluate the efficacy of ta-VNS in preventing emergence agitation and delirium 
following tonsillectomy and adenoidectomy in children. This study aims to provide a safe and non-
invasive intervention for the prevention of ED in pediatric anesthesia and to offer new theoretical 
and clinical evidence supporting the use of neuromodulation in perioperative management. 
Study Objective 
To investigate the effect of transcutaneous auricular vagus nerve stimulation (ta-VNS) on 
emergence agitation (EA) and emergence delirium (ED) in children undergoing 
adenotonsillectomy. 
Study Design and Methods 
Study Population 
This study will enroll pediatric patients scheduled for elective adenotonsillectomy under general 
anesthesia. The inclusion and exclusion criteria are as follows: 
Inclusion Criteria 
1. Children aged 3 to 8 years. 
2. Diagnosed with tonsillar and/or adenoidal hypertrophy at The First Affiliated Hospital of 
Zhejiang Chinese Medical University, and scheduled to undergo adenotonsillectomy 

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under sevoflurane inhalational general anesthesia. 
3. Classified as American Society of Anesthesiologists (ASA) physical status I–II. 
4. Able to understand the study procedures and assessment scales, and communicate 
effectively with the research staff. 
Exclusion Criteria 
1. Children with ASA physical status III–IV, or with hepatic, renal, cardiovascular, or 
endocrine dysfunction. 
2. Children with neuromuscular diseases or left auricular dermatitis. 
3. Recent respiratory tract infection, developmental delay, or autism. 
4. Children receiving specialized institutional care or living in social welfare facilities, or 
with any other condition that may interfere with study participation. 
5. Participation in other ongoing clinical trials. 
Study Content 
Participant Grouping, Intervention, and Blinding 
After obtaining written informed consent from the child’s legal guardian, participants will be 
randomly assigned in a 1:1 ratio to either the active stimulation group or the sham stimulation group 
using a computer-generated random number table. Randomization will be completed prior to the 
first preoperative intervention. Group allocation information will be kept confidential by the study 
designer, while both the implementers and data analysts will remain blinded to group assignments 
to ensure a double-blind design.The sham stimulation device will be identical in appearance, 
wearing method, and operation procedure to the active stimulation device to ensure participants 
cannot distinguish the stimulation type. 
In the active stimulation group, participants will receive active electrical stimulation on the 
left cymba conchae. The stimulation parameters are as follows: frequency 25 Hz, pulse width 300 
μs, 30 s on/30 s off alternating mode. The stimulation will last for three consecutive days: 
1. The first stimulation begins in the preoperative preparation area, applied by the guardian 
or parent under supervision. 
2. The stimulation continues intraoperatively and in the post-anesthesia care unit (PACU). 
3. The device will be turned off and removed upon discharge from PACU. 
The stimulation intensity will start at level 1 and increase by one level at a time (each level ≈ 
0.4 V) until the child reports a tingling sensation, after which the intensity will be adjusted to the 
highest comfortable level without pain. On postoperative days 1 and 2, stimulation will be applied 
twice daily (morning and afternoon), each lasting 30 minutes. An operator must be present 
throughout each stimulation session to supervise. 

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The sham group will receive an identical procedure, with electrodes placed on the left cymba 
conchae and stimulation adjusted similarly before being turned off. To monitor compliance, 
nursing staff will record the start and end time of each stimulation, completion of device 
placement, and child cooperation during the intervention. 
Anesthesia Protocol 
Standard monitoring includes continuous ECG, pulse oximetry (SpO₂), bispectral index (BIS), 
and noninvasive blood pressure, initiated before induction and recorded every 5 minutes.Anesthesia 
will be induced with fentanyl (2–2.5 μg·kg⁻¹), propofol (2–2.5 mg·kg⁻¹), and rocuronium bromide 
(0.6 mg·kg⁻¹), with 100% oxygen (4 L·min⁻¹). After successful induction and complete muscle 
relaxation, tracheal intubation will be performed using a video laryngoscope. 
During anesthesia maintenance, the sevoflurane concentration (2–4%) will be dynamically 
adjusted to maintain BIS around 50 (range 40–60) and vital signs within ± 20% of baseline. The gas 
mixture will consist of air/oxygen (50%) at a flow rate of 2 L·min⁻¹. The end-tidal CO₂ (PETCO₂) 
will be maintained at 35–45 mmHg by adjusting the respiratory rate and tidal volume.If blood 
pressure or heart rate exceeds 20% of baseline and inadequate anesthesia is excluded, fentanyl 0.5–
1 μg·kg⁻¹ may be administered as needed.At the end of surgery, all anesthetic agents will be 
discontinued, and neuromuscular blockade will be antagonized using sugammadex sodium. 
Outcome Measures (All Are Routine Clinical Assessments) 
a. Primary Outcome 
(1) Incidence of Emergence Delirium (ED) 
ED will be diagnosed when the Pediatric Anesthesia Emergence Delirium (PAED) score is ≥10 
and the FLACC (Face, Legs, Activity, Cry, Consolability) score is <4.If the PAED score ≥10 and 
FLACC score ≥4, the child will first receive analgesic treatment: when FLACC ≥4, fentanyl 0.5 
μg·kg⁻¹ will be administered intravenously.Five minutes after analgesia, the evaluation will be 
repeated.If the PAED score remains ≥10 after reassessment, ED will be confirmed regardless of 
the FLACC score35. 
b. Secondary Outcomes 
(1) Incidence of Postoperative Pain 
Defined as FLACC score ≥4. 
FLACC scores will be assessed at 0, 5, 10, 20, and 30 minutes after anesthesia emergence. 
(2) Quality of Recovery in Children 
On postoperative days 1–2, the Pediatric Quality of Recovery (PedSQoR) scale will be used to 

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evaluate postoperative recovery. 
The PedSQoR (20-item) questionnaire comprehensively reflects children’s physical, emotional, 
and psychological recovery after surgery and anesthesia. 
Proxy Report: for children aged 2–7 years, completed by parents or caregivers. 
Self-Report: for children aged 8–17 years, completed by the child. 
The total score ranges from 20 to 100, with higher scores indicating better recovery 
quality36. 
(3) Recovery Time 
Defined as the time interval from cessation of sevoflurane to the moment the child awakens and 
responds to their name when called in a normal tone, including any delay due to ED. 
(4) Adverse Events 
All adverse events during hospitalization will be recorded, including nausea, vomiting, 
pneumonia, and ta-VNS–related complications. 
Sample Size Estimation 
According to previous studies, the incidence of emergence delirium (ED) after tonsillectomy 
and adenoidectomy under sevoflurane anesthesia in children is approximately 44%.This study 
hypothesizes that ta-VNS will reduce the postoperative ED incidence to 20% in the intervention 
group.Using G*Power software (version 3.1.9.7), the required sample size is calculated to be 110 
participants.Considering an estimated 10% dropout rate, a total of 120 children will be enrolled, 
with 60 participants in each group. 
Research flowchart 

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Data Management and Confidentiality 
A paper-based Case Report Form (CRF) will be designed to record clinical data and study 
results. All data will be stored on password-protected computers to ensure the confidentiality of 
patient privacy. The study will be conducted in strict accordance with the principles of Good 
Clinical Practice (GCP). 
    Only investigators authorized by the principal investigator will have access to review or 
analyze the data. Computers used for data management will be password-protected, and all paper 
records will be securely locked. 
    All information related to the identity of the participants will remain confidential and will not 
be disclosed to any third party beyond the scope permitted by relevant laws and/or regulations. 
Informed Consent 
Before enrollment, the investigator responsible for obtaining informed consent will provide 
the participant’s guardian or parents with a complete and detailed written explanation of the 
study’s purpose, nature, procedures, and possible benefits and risks. Participants will be informed 

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that they have the right to withdraw from the study at any time.Prior to inclusion, each participant 
must be fully informed and given sufficient time to decide whether to participate. Only those 
whose guardians or parents voluntarily agree and sign the informed consent form will be enrolled 
in this study. 
Adverse Events and Management 
Transcutaneous auricular vagus nerve stimulation (taVNS) is a selective, non-invasive, and 
low-risk form of vagus nerve stimulation. The main adverse events include mild pain, flu-like 
symptoms, and local skin discomfort, all of which typically resolve after discontinuation of 
taVNS. To date, no serious adverse events related to taVNS have been reported in the literature. 
In the event of any harm or adverse reaction, the research team will provide participants with 
prompt and appropriate medical care. 
 
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