Brain Tissue Integrity and Autonomic Function Alterations in Childhood OSA and ADHD, and After Adenotonsillectomy.

NCT04732572 | Unknown DMC

• 1 other identifier: 201902118A3
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Obstructive sleep apnea (OSA) and attention-deficit/hyperactivity disorder (ADHD) are two common, severe disorders in children. Unfortunately, pediatric OSA is closely associated with ADHD, and both diseases can cause cognitive impairment, behavior problems, and low academic performance. OSA can damage the brain and induce autonomic dysfunction, and then cause cognitive, behavioral, and quality-of-life problems. The presence of ADHD can further exacerbate these adverse effects of OSA. Therefore, the identification of robust biomarkers of OSA and ADHD is a key imperative to facilitate early identification of the pathological features and mechanisms and to optimize the treatment of OSA and ADHD for the pediatric population. Diffusion MRI of the brain is one of the most widely used technology for assessment of brain tissue integrity and heart rate variability is one of the most widely used measurements of autonomic function. However, the effects of ADHD and adenotonsillectomy on MRI and HRV biomarkers in children with OSA have not been reported. We hypothesize that comorbid ADHD can deteriorate brain damage and autonomic dysfunction, and adenotonsillectomy can reverse these alternations in children with OSA. The aims of this study are (1) to investigate the differences in pediatric brain tissue integrity, autonomic function, attention, behavior, quality-of-life, and sleep factors between the 'OSA with ADHD', 'OSA without ADHD', and 'healthy control' group; (2) to evaluate the efficacy of adenotonsillectomy versus watchful waiting with supportive care, with respect to the same variables of interest; (3) to evaluate whether the relative efficacy of the treatment differs according to baseline ADHD, weight, or OSA severity; and (4) to develop a predictive model for surgical success rate using both conventional well-known factors and MRI/HRV biomarkers. This is a 3-year prospective study that includes two parts. The Part I study is a cross-sectional study recruiting 100 children (5 to 9 years of age) to investigate the differences in brain tissue integrity (voxel-based morphometry and fractional anisotropy; assessed by structure MRI \[T1\] for volumetric alternations of gray and white matter, resting-state functional MRI for functional connectivity, and diffusion MRI for white matter integrity), autonomic function (time-domain and frequency-domain analyses; assessed by a wearable, real-time HRV measurement), severity pf attentive and behavioral problems (assessed by the Swanson, Nolan and Pelham IV-Teacher and Parent Rating Scale), quality-of-life (assessed by OSA-18), and sleep factors (apnea-hypopnea index, obstructive apnea index, arousal index, mean and least oxygen saturation, and sleep stage; assessed by polysomnography) between the OSA with ADHD group (Study Group 1; n = 40), the OSA without ADHD group (Study Group 2; n = 40), and the healthy control group (Control Group; n = 20). The Part II study is a randomized controlled trial includes a total of 64 children with OSA (32 children will be recruited from Study Group 1 and Study Group 2, respectively). We randomly assigned (1:1) these 64 pediatric patients with OSA to adenotonsillectomy or a strategy of watchful waiting with supportive care, matched by ADHD, obesity, and severe OSA. Variables of interest using the same methodology are assessed at baseline and at 7 months.

Conditions

Attention-deficit/Hyperactivity Disorder; Autonomic Nervous System Imbalance; Obstructive Sleep Apnea of Child

Keywords

brain magnetic resonance imaging; brain tissue integrity; heart rate variability

Outcome Measures

Primary Outcomes (1)

• The total score of the Swanson, Nolan and Pelham IV (SNAP-V) questionnaires.

  We assess the ADHD severity using the SNAP-IV-Parent and Teacher questionnaires at baseline and 7 months after adenotonsillectomy (Arm 1) or allocation (Arm 2). The SNAP-IV, a 26-item scale, consists of Inattention (Items 1-9) and Hyperactivity/Impulsivity (Items 10-18), and Oppositionality (Items 19-26), corresponding to the core symptoms of DSM-IV ADHD and oppositional defiant disorder (ODD), respectively. The 26 items of the SNAP-IV are rated on a four-point Likert scale, with scores of 0-3 representing ''not at all,'' ''just a little,'' ''quite a bit,'' and ''very much,'' respectively. The Chinese SNAP-IV-Parent and -Teacher Forms have good validity and reliability. It will need 10 min to complete the SNAP-IV questionnaire. A summary score is calculated that ranges from 0 (no impact on attention, behavior, and cooperation) to 78 (major negative impact).

  The SNAP-IV-Teacher and Parent Rating Scale questionnaires will be provided at baseline and at 7 months.

Secondary Outcomes (5)

• Brain tissue integrity.

  The brain tissue integrity will be assessed at baseline and at 7 months.

• Autonomic function.

  The autonomic function will be assessed at baseline and at 7 months.

• The attention-deficit/hyperactivity disorder (ADHD) severity.

  The SNAP-IV-Teacher and Parent Rating Scale questionnaires will be provided at baseline and at 7 months.

• The obstructive sleep apnea (OSA)-related quality-of-Life.

  The OSA-18 questionnaires will be provided at baseline and at 7 months.

• Sleep

  The participants will undergo polysomnography at baseline and at 7 months.

Study Arms (2)

Adenotonsillectomy

EXPERIMENTAL

Within 1 to 4 weeks (30 days) of randomization, participants randomized to the adenotonsillectomy arm will undergo surgery under general anesthesia, as occurs as part of routine standard of care.

Behavioral: Sleep and healthy lifestyle education; Other: Other supportive care; Procedure: Adenotonsillectomy

Watchful waiting with supportive care

ACTIVE COMPARATOR

Within 1 to 4 weeks after the 7-month visit, participants in the Arm 2 group will be referred for re-evaluation of surgical candidacy. Symptoms and polysomnographic findings (baseline and month 7) will be reviewed by the ENT and a decision whether to proceed with adenotonsillectomy as part of routine clinical care will be made.

Behavioral: Sleep and healthy lifestyle education; Other: Other supportive care

Interventions

Sleep and healthy lifestyle education BEHAVIORAL

Participants in both groups will receive age-appropriate standardized educational material for both Optimal Sleep Hygiene and Healthy Habits. Educational play will also be encouraged by providing take-home materials. Participant and parent/legal guardian (s) will be given verbal and written directions on the use of these materials at the time of the visit. Research Coordinators will encourage and track utilization of the sleep hygiene educational tools during the trial.

Adenotonsillectomy; Watchful waiting with supportive care

Other supportive care OTHER

Throughout the course of the trial participants identified by the principal investigator as having suboptimal asthma or rhinitis will be referred to their primary care physician for management and further treatment of these problems. All participants will receive a generic brand of an over-the-counter saline nasal spray to use as needed for nasal dryness and crusting. Proper use of the spray will be reviewed and demonstrated by the research coordinator at the baseline visit.

Adenotonsillectomy; Watchful waiting with supportive care

Adenotonsillectomy PROCEDURE

Surgery will be performed by board-certified otolaryngologists with or without the assistance of resident physicians in accredited otolaryngology training programs. Prior to the surgical procedure, tonsillar size will be graded using a standardized scale of 0-4. Extent of adenoid tissue will also be graded as mild (0-33%), moderate (34-66%) or severely (67-100%) obstructing the posterior choanae. Complete bilateral tonsillectomy and removal of obstructing adenoid tissue will be performed by cold dissection, monopolar electrocautery or plasma knife-assisted surgical technique under general anesthesia. All procedures will be performed using inpatient facility for 3-4 days.

Adenotonsillectomy

Eligibility Criteria

• Age: 5 Years - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Ages 5.0 to 9.99 years at time of screening.
• Diagnosis of OSA with ADHD, OSA without ADHD, or non-snoring with typical development:
• ) Diagnosed with OSA defined as: OAI ≥1 event/h or AHI ≥2 events/h, confirmed on nocturnal, laboratory-based polysomnography and parental report of habitual snoring (on average occurring \>3 nights per week).
• ) Diagnosed with ADHD defined as: Six or more of (1) inattentive symptoms (nine symptoms), (2) hyperactive and impulsive symptoms (nine symptoms) or (3) combined inattentive, hyperactive and impulsive symptoms must be present for at least 6 months, be inconsistent with the child's developmental level, and have a negative effect on their social and academic activities.
• ) Diagnosed with non-snoring with typical development defined as parental report of no habitual snoring (on average occurring ≤3 nights per week), \<6 inattentive symptoms, \<6 hyperactive and impulsive symptoms, and being consistent with the child's developmental level.
• Tonsillar hypertrophy ≥1 based on a standardized scale of 0-4 (0 = surgically absent; 1 = taking up \<25% of the airway; 2 = 25-50 % of the airway; 3 = 50-75 % of the airway; 4 = \>75% of the airway).
• Deemed to be a surgical candidate for adenotonsillectomy for OSA by ENT evaluation (the Part II study).

You may not qualify if:

• Recurrent tonsillitis that meets published ENT clinical practice guidelines for surgery defined as: \> 3 episodes in each of 3 years, 5 episodes in each of 2 years, or 7 episodes in one year.
• Craniofacial anomalies, including cleft lip and palate or sub-mucosal cleft palate or any anatomic or systemic condition which would interfere with general anesthesia or removal of tonsils and adenoid tissue in the standard fashion.
• Obstructive breathing while awake that merits prompt adenotonsillectomy in the opinion of the child's physician.
• Severe OSA or significant hypoxemia requiring immediate adenotonsillectomy as defined by: OAI \>20 events/h or AHI \>30 events/h or SpO2 \<90% for more than 2% sleep time
• Evidence of clinically significant cardiac arrhythmia, extremely overweight (body mass index \[BMI\] z-score \> 2.99), severe health problems that could be exacerbated by delayed treatment for OSA (such as heart disease, cor pulmonale, poorly controlled asthma, epilepsy required medication, diabetes, mental retardation), current use ADHD or psychotropic medication(s), and previous upper airway surgery.
• A family planning to move out the area within the year.

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead
• Ministry of Science and Technology, Taiwan: collaborator

Study Sites (1)

Li-Ang Lee

Taoyuan District, 33305, Taiwan

RECRUITING

Related Publications (5)

• Hayano J, Yuda E. Pitfalls of assessment of autonomic function by heart rate variability. J Physiol Anthropol. 2019 Mar 13;38(1):3. doi: 10.1186/s40101-019-0193-2.

  PMID: 30867063 BACKGROUND

• Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, Mitchell RB, Amin R, Katz ES, Arens R, Paruthi S, Muzumdar H, Gozal D, Thomas NH, Ware J, Beebe D, Snyder K, Elden L, Sprecher RC, Willging P, Jones D, Bent JP, Hoban T, Chervin RD, Ellenberg SS, Redline S; Childhood Adenotonsillectomy Trial (CHAT). A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med. 2013 Jun 20;368(25):2366-76. doi: 10.1056/NEJMoa1215881. Epub 2013 May 21.

  PMID: 23692173 RESULT

• Horne RSC, Roy B, Walter LM, Biggs SN, Tamanyan K, Weichard A, Nixon GM, Davey MJ, Ditchfield M, Harper RM, Kumar R. Regional brain tissue changes and associations with disease severity in children with sleep-disordered breathing. Sleep. 2018 Feb 1;41(2):zsx203. doi: 10.1093/sleep/zsx203.

  PMID: 29267958 RESULT

• Somuk BT, Bozkurt H, Goktas G, Demir O, Gurbuzler L, Eyibilen A. Impact of adenotonsillectomy on ADHD and nocturnal enuresis in children with chronic adenotonsillar hypertrophy. Am J Otolaryngol. 2016 Jan-Feb;37(1):27-30. doi: 10.1016/j.amjoto.2015.08.003. Epub 2015 Aug 23.

  PMID: 26700255 RESULT

• O'Driscoll DM, Horne RS, Davey MJ, Hope SA, Anderson V, Trinder J, Walker AM, Nixon GM. Increased sympathetic activity in children with obstructive sleep apnea: cardiovascular implications. Sleep Med. 2011 May;12(5):483-8. doi: 10.1016/j.sleep.2010.09.015.

  PMID: 21521626 RESULT

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity

Interventions

Sleep

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Nervous System Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Li-Ang Lee, M.D., M.Sc.

  Chang Gung Memorial Hospital, Linkou Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Li-Ang Lee, M.D., M.Sc.

CONTACT

886-33281200; 5738@cgmh.org.tw

Hai-Hua Chuang, M.D.

CONTACT

886-975366509; chhaihua@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The investigators will be blinded to the intervention group while they perform outcome assessment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants in the Part II study will receive the following interventions throughout the course of the trial: (1) sleep and healthy lifestyle education, and (2) other supportive care. Arm 1 - Adenotonsillectomy Within 1 to 4 weeks (30 days) of randomization, participants randomized to the adenotonsillectomy arm will undergo surgery under general anesthesia, as occurs as part of routine standard of care. Surgery will be performed by board-certified otolaryngologists with or without the assistance of resident physicians in accredited otolaryngology training programs. Arm 2 - Watchful waiting with supportive care Within 1 to 4 weeks after the 7-month visit, participants in the Arm 2 group will be referred for re-evaluation of surgical candidacy. Symptoms and polysomnographic findings (baseline and month 7) will be reviewed by the ENT and a decision whether to proceed with adenotonsillectomy as part of routine clinical care will be made.

Study Record Dates

• First Submitted: January 27, 2021
• First Posted: February 1, 2021
• Study Start: August 1, 2020
• Primary Completion: July 31, 2023
• Study Completion: October 30, 2023
• Last Updated: February 1, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)