Transcutaneous Auricular Vagus Nerve Stimulation for Prevention of Emergence Agitation and Delirium in Children Undergoing Tonsillectomy and Adenoidectomy

Official title

Transcutaneous Auricular Vagus Nerve Stimulation for Preventing Emergence Agitation and Delirium After Pediatric Tonsillectomy and Adenoidectomy: A Randomized, Double-Blind, Interventional Study

Overview

Brief Summary This study is designed to find out whether transcutaneous auricular vagus nerve stimulation (taVNS) can safely reduce restlessness and confusion when children wake up from anesthesia after tonsillectomy and adenoidectomy. These problems, called emergence agitation and delirium, are common after surgery and can cause distress for both children and their families.TaVNS is a non-invasive treatment that delivers mild electrical stimulation to a specific area of the ear connected to the vagus nerve. It does not involve needles or medication, and children usually feel only a gentle tingling sensation.In this randomized, double-blind study, children will be assigned by chance to receive either taVNS or a sham (placebo) stimulation during surgery. Neither the children, their families, nor the medical team providing care will know which treatment each child receives.Researchers will observe and record how calmly children wake up from anesthesia, whether they show signs of delirium, and any side effects. The goal of this study is to test whether taVNS is an effective and safe way to improve recovery and comfort for children after surgery.

Detailed description

Background and Rationale Emergence delirium (ED) in pediatric patients is a common postoperative complication linked to exposure to volatile anesthetics, particularly sevoflurane. The proposed mechanism involves dysregulation of the autonomic nervous system, characterized by reduced vagal tone and sympathetic hyperactivity. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique designed to increase vagal activity by delivering low-intensity electrical currents to the auricular branch of the vagus nerve in the ear. Preclinical and clinical evidence suggests taVNS can exert anti-inflammatory, analgesic, and anxiolytic effects via central and peripheral pathways. This trial is designed to investigate whether perioperative taVNS can mitigate ED by modulating autonomic balance.

Intervention and Blinding Methodology The study employs a double-blind, sham-controlled design. Active and sham stimulation devices are physically identical. The active device delivers electrical stimulation with parameters set at a frequency of 25 Hz, a pulse width of 300 μs, and a cyclic mode of 30 seconds on followed by 30 seconds off. Stimulation intensity is individually titrated to a perceptible but non-painful tingling sensation. The sham device follows an identical placement and titration procedure but ceases output after the initial adjustment phase. This methodology ensures participants, caregivers, and outcome assessors are blinded to group assignment. Stimulation is initiated in the preoperative holding area, continues intraoperatively, and concludes upon discharge from the post-anesthesia care unit (PACU). Supplemental stimulation sessions are administered on postoperative days 1 and 2.

Study Procedures Overview Following enrollment and randomization, the stimulation device is applied to the left auricular concha. Standardized general anesthesia is administered per protocol, utilizing sevoflurane for maintenance with titration guided by bispectral index (BIS) monitoring. Intraoperative vital signs and anesthetic depth are recorded. Upon cessation of anesthetics, continuous behavioral observation begins in the PACU.

Technical and Mechanistic Considerations The selection of the left auricle for stimulation is based on anatomical studies indicating a lower density of cardiac vagal fibers compared to the right side. The chosen stimulation parameters (25 Hz, 300 μs) are derived from prior neurophysiology studies suggesting efficacy in activating afferent vagal pathways. The cyclic on/off pattern is intended to prevent nerve accommodation. The perioperative timing of stimulation is designed to preemptively modulate autonomic tone prior to the emergence phase, a period of high neurophysiological lability.

Data Collection and Management Primary and secondary outcome data are collected at predetermined time points by trained, blinded assessors. Data pertaining to device adherence (session timing, wear status) are recorded by nursing staff. All data are entered into a secure, electronic data capture system. Source data verification is performed per the monitoring plan.

Statistical Considerations The primary analysis will utilize the intention-to-treat principle. The primary endpoint, incidence of emergence delirium, will be compared between groups using a chi-square test. A secondary logistic regression analysis will adjust for predefined covariates (e.g., age, surgery duration) to evaluate the independent effect of the intervention. Analysis of continuous secondary endpoints will employ t-tests or non-parametric equivalents based on data distribution. A two-sided p-value \<0.05 will define statistical significance.

Safety Monitoring Adverse events are monitored from device application through the follow-up period. Specific attention is given to local skin reactions at the electrode site and any potential device-related incidents. All adverse events are documented and reported according to the protocol and regulatory requirements.

Significance and Implications This investigation aims to provide high-level evidence on the efficacy of a non-pharmacologic, neuromodulatory approach to preventing pediatric emergence delirium. Positive results could establish taVNS as a viable strategy to enhance postoperative recovery and safety, with potential implications for broadening the application of bioelectronic medicine in perioperative care.

Interventions

• Device Active taVNS Group
  Active taVNS Group：The taVNS device delivers electrical stimulation via an ear-clip electrode placed on the left cymba conchae.Parameters: 25 Hz frequency, 300 µs pulse width, 30 s ON / 30 s OFF duty cycle.Applied from pre-induction through postoperative recovery, then twice daily for 30 min on POD 1-2.Intensity adjusted to induce mild tingling without discomfort.
• Device Sham stimulation group
  The sham stimulation device is visually identical to the active taVNS unit. Electrodes are placed on the same auricular site, and procedures mimic active stimulation, but no electrical current is delivered.Used to maintain blinding and control for placebo effects.

Primary outcome measures

• The incidence of emergence delirium (ED) [Time frame: Every 10 min during after the patient removed the endotracheal tube ，in the first 30 min in the Post-Anesthesia Care Unit (PACU).]

Secondary outcome measures (4)

• The incidence of postoperative pain [Time frame: Assessed at 0, 5, 10, 20, and 30 minutes after emergence from anesthesia.]
• Quality of Recovery in Children (PedS-QoR Score) [Time frame: Assessed at 24 and 48 hours after surgery.]
• Recovery Time [Time frame: Recovery parameters were assessed every 5 min in the first 30 min after anesthesia discontinuation and then every 10 min until discharge criteria were met or up to 120 min.]
• Adverse Events [Time frame: From initiation of the intervention through 3 days after surgery.]

Eligibility criteria

Inclusion criteria

• Children aged 3 to 8 years.
• Patients receiving care at The First Affiliated Hospital of Zhejiang Chinese Medical University with a diagnosis of tonsil and/or adenoid hypertrophy, scheduled for tonsillectomy and/or adenoidectomy under sevoflurane inhalation general anesthesia.
• American Society of Anesthesiologists (ASA) physical status I-II.
• Ability to understand the study procedures and assessment scales, and to communicate effectively with study personnel.

Exclusion criteria

• ASA physical status III-IV, or presence of hepatic or renal dysfunction, cardiovascular disease, or endocrine disorders.
• Neuromuscular disorders or dermatitis of the left auricle.
• Recent respiratory infection, developmental delay, or autism spectrum disorder.
• Receipt of specialized care, residence in social welfare institutions, or any other condition that may interfere with study participation.
• Current enrollment in another clinical trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Prevention

Study locations

China · 1 center

• The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial — Hangzhou

Publications

• Graydon C, Stricker PA, Kelleher S, Cravero J, Karim N, Muhly WT, Lee-Archer P. Development of the Pediatric Scale for Quality of Recovery (PedSQoR). Anesthesiology. 2025 Aug 1;143(2):275-286. doi: 10.1097/ALN.0000000000005503. Epub 2025 Apr 14. PMID 40227959
• Cai YH, Zhong JW, Ma HY, Szmuk P, Wang CY, Wang Z, Zhang XL, Dong LQ, Liu HC. Effect of Remimazolam on Emergence Delirium in Children Undergoing Laparoscopic Surgery: A Double-blinded Randomized Trial. Anesthesiology. 2024 Sep 1;141(3):500-510. doi: 10.1097/ALN.0000000000005077. PMID 38758221
• Badran BW, Brown JC, Dowdle LT, Mithoefer OJ, LaBate NT, Coatsworth J, DeVries WH, Austelle CW, McTeague LM, Yu A, Bikson M, Jenkins DD, George MS. Tragus or cymba conchae? Investigating the anatomical foundation of transcutaneous auricular vagus nerve stimulation (taVNS). Brain Stimul. 2018 Jul-Aug;11(4):947-948. doi: 10.1016/j.brs.2018.06.003. Epub 2018 Jun 6. No abstract available. PMID 29895444
• May SM, Reyes A, Martir G, Reynolds J, Paredes LG, Karmali S, Stephens RCM, Brealey D, Ackland GL. Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing noncardiac surgery: prospective observational mechanistic cohort study. Br J Anaesth. 2019 Dec;123(6):758-767. doi: 10.1016/j.bja.2019.08.003. Epub 2019 Sep 3. PMID 31492527
• Abbott TEF, Pearse RM, Cuthbertson BH, Wijeysundera DN, Ackland GL; METS study investigators. Cardiac vagal dysfunction and myocardial injury after non-cardiac surgery: a planned secondary analysis of the measurement of Exercise Tolerance before surgery study. Br J Anaesth. 2019 Feb;122(2):188-197. doi: 10.1016/j.bja.2018.10.060. Epub 2018 Dec 17. PMID 30686304
• Wang X, Huang ZG, Gold A, Bouairi E, Evans C, Andresen MC, Mendelowitz D. Propofol modulates gamma-aminobutyric acid-mediated inhibitory neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Anesthesiology. 2004 May;100(5):1198-205. doi: 10.1097/00000542-200405000-00023. PMID 15114218
• May SM, Chiang E, Reyes A, Martir G, Patel A, Karmali S, Patel S, West S, Del Arroyo AG, Gourine AV, Ackland GL. Neuromodulation of innate immunity by remote ischaemic conditioning in humans: Experimental cross-over study. Brain Behav Immun Health. 2021 Jul 15;16:100299. doi: 10.1016/j.bbih.2021.100299. eCollection 2021 Oct. PMID 34589791
• Ackland GL, Abbott TEF, Cain D, Edwards MR, Sultan P, Karmali SN, Fowler AJ, Whittle JR, MacDonald NJ, Reyes A, Paredes LG, Stephens RCM, Del Arroyo AG, Woldman S, Archbold RA, Wragg A, Kam E, Ahmad T, Khan AW, Niebrzegowska E, Pearse RM. Preoperative systemic inflammation and perioperative myocardial injury: prospective observational multicentre cohort study of patients undergoing non-cardiac sur PMID 30686303

Identifiers

NCT: NCT07394647 · MR-33-25-067114

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗