Key Points
Question
Can the hypoglossal nerve stimulator be safely implanted in children with Down syndrome, and is it effective in alleviating nocturnal airway obstruction?
Findings
In this case series of the first 6 children to receive the hypoglossal nerve stimulator implant, stimulation was well tolerated and resulted in a reduction in apnea hypopnea index, as well as improvement in quality of life.
Meaning
The hypoglossal nerve stimulator is a potential therapeutic option for adolescents with Down syndrome and severe obstructive sleep apnea.
This case series examines whether hypoglossal nerve stimulation is safe and effective in children with Down syndrome and obstructive sleep apnea.
Abstract
Importance
Obstructive sleep apnea (OSA) affects up to 60% of children with Down syndrome (DS) and may persist in half of patients after adenotonsillectomy. Children with DS who have persistent OSA often do not tolerate treatment with positive pressure airway support devices or tracheotomy for their residual moderate to severe OSA. The hypoglossal nerve stimulator is an implantable device that delivers an electrical impulse to anterior branches of the hypoglossal nerve in response to respiratory variation, resulting in tongue base protrusion that alleviates upper airway obstruction in adults.
Objective
To determine whether hypoglossal nerve stimulation is safe and effective in children with DS.
Design, Setting, and Participants
Case series of the first 6 adolescents with DS to undergo hypoglossal nerve stimulator implantation. Participants were 6 children and adolescents (12-18 years) with DS and severe OSA (apnea hypopnea index [AHI] > 10 events/h) despite prior adenotonsillectomy.
Intervention
Inspire hypoglossal nerve stimulator placement.
Main Outcomes and Measures
Patients were monitored for adverse events. Adherence to therapy was measured by hours of use recorded by the device. Efficacy was evaluated by comparing AHI and OSA-18, a validated quality-of-life instrument, scores at baseline and follow-up.
Results
In 6 patients (4 male, 2 female; aged 12-18 years), hypoglossal nerve stimulator therapy was well tolerated (mean use, 5.6-10.0 h/night) and effective, resulting in significant improvement in OSA. At 6- to 12-month follow-up, patients demonstrated a 56% to 85% reduction in AHI, with an overall AHI of less than 5 events/h in 4 children and less than 10 events/h in 2 children. Children also demonstrated a clinically significant improvement (mean [SD] overall change score, 1.5 [0.6]; range, 0.9-2.3) on the OSA-18, a validated quality-of-life instrument.
Conclusions and Relevance
Hypoglossal nerve stimulation was well tolerated and effective in the study population, representing a potential therapeutic option for patients with DS and refractory OSA after adenotonsillectomy who are unable to tolerate positive pressure airway devices.
Trial Registration
clinicaltrials.gov Identifier: NCT2344108
Introduction
Obstructive sleep apnea (OSA) affects up to 5.7% of the general pediatrics population and up to 80% of patients with Down syndrome (DS). In children, OSA is associated with adverse behavior and quality of life (QOL), as well as cardiopulmonary complications. In children with adenotonsillar hypertrophy, adenotonsillectomy (T&A) is the initial treatment of choice. However, more than 60% of children with DS will demonstrate persistent airway obstruction after T&A due to reduced muscle tone, macroglossia, maxillary hypoplasia, and lingual tonsil hypertrophy.
Positive pressure airway support treatments, supplemental oxygen delivery, oromaxillofacial surgery, and, in severe cases, tracheotomy are often required to treat residual airway obstruction; however, these treatments are problematic. Although they are effective when used properly, many children do not adhere to noninvasive airway support therapy, with some series demonstrating high dropout rates and nonadherence rates ranging from 40% to 50%. Tracheotomy bypasses upper airway obstruction completely; however, it is associated with a host of short-term and long-term complications in up to 19% of patients, including risks of accidental decannulation, wound breakdown, formation of suprastomal granulation tissue and collapse, and, rarely, life-threatening hemorrhage from tracheoinominate fistula formation and death. Additionally, for caregivers, pediatric tracheotomy is associated with substantial caregiver burden and reduced mental health.
The hypoglossal nerve stimulator (Inspire Medical Systems) is an implantable device that, using a sensing electrode placed between the intercostal muscles and stimulation lead placed around anterior branches of the hypoglossal nerve, delivers electrical impulses to tongue protrusor muscles at the time of inspiration, alleviating upper airway obstruction. In neurotypical adults with moderate OSA and an apnea hypopnea index (AHI) of less than 50 events/h, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) less than 32, and without circumferential airway collapse at the level of the velopharynx, hypoglossal nerve stimulation has been shown to be an effective treatment for OSA. In adults, prospective studies demonstrate that therapy remains well tolerated and effective up to 36 months after implantation.
Given the prevalence of persistent OSA after T&A in patients with DS, as well as anatomic considerations in this population, we developed a pilot study to primarily evaluate the safety of hypoglossal nerve stimulation in children with DS and residual OSA after T&A. Safety data, including perioperative complications, and tolerance of hypoglossal nerve stimulation were collected. As a secondary outcome, adherence to therapy and efficacy data were also collected. Here we present 6-month and 1-year follow-up data of the first 6 pediatric patients to ever receive the hypoglossal nerve stimulator implant.
Methods
This study was approved by the institutional review board at Massachusetts Eye and Ear Infirmary, Harvard Medical School, as well as by the US Food and Drug Administration, which issued an investigational device exemption. Verbal assent was obtained from all patients, and written consent was obtained from study participants or their legal guardians prior to study participation and nerve stimulator implantation. As part of this pilot study, we were approved to enroll 6 adolescents and young adults, 10 to 21 years of age, with DS and refractory OSA after T&A who were unable to tolerate continuous positive airway pressure (CPAP) or dependent on a tracheotomy at night. Patients were identified as candidates for implantation by the DS clinic at our institution and underwent initial evaluation by the surgical team. Patients with any medical conditions necessitating future magnetic resonance imaging were excluded because the current generation of the device is incompatible with magnetic resonance imaging. Parents also had to attest to their child’s ability to cooperate with examinations and communicate discomfort. To participate, patients had to be medically stable with a BMI of less than 32. Patients without a polysomnogram (PSG) within 6 months underwent PSG to identify baseline characteristics and verify inclusion criteria, including AHI between 10 and 50 events/h and a central apnea contribution of less than 25%. Patients meeting PSG criteria then underwent drug-induced sleep endoscopy (DISE) under sedation with propofol and/or dexmedetomidine, at the discretion of supervising anesthesiologists, to evaluate upper airway anatomy at the level of the velopharynx, oropharynx, tongue base, and hypopharynx. Examination findings were evaluated using the VOTE (velopharynx, oropharynx including the palatine tonsils, tongue, and epiglottis) classification scheme, which has been described previously. Circumferential collapse at the level of the velopharynx would exclude a patient from study participation. Objective inclusion criteria, including BMI, PSG findings, and anatomic findings, were based on the inclusion criteria used in prior studies of the hypoglossal nerve stimulator in adult patients.
Study participants meeting inclusion criteria then underwent hypoglossal nerve stimulator implantation using standard techniques, which have been described previously. Briefly, the hypoglossal nerve stimulator is implanted through 3 incisions. The hypoglossal nerve is exposed through a submental incision and its anterior branches are dissected with the aid of electromyographic potential monitoring to identify branches to include within the cuff of a stimulating electrode. An impulse generator is placed in the right chest superficial to the pectoralis through an incision below the clavicle, much like a cardiac pacemaker. Finally, a third incision in the right thorax is made to place a pleural sensing lead between the internal and external intercostal muscles. All patients underwent postoperative posterior-anterior and lateral chest radiography to rule out pneumothorax and to document device position. All participants received perioperative antibiotics and were hospitalized overnight for monitoring.
One month after implantation, the nerve stimulators were activated in the clinic then turned off. The evening of the clinic appointment, patients underwent titration of their devices during an overnight PSG, then were discharged to use therapy nightly to become acclimated to the device. Follow-up PSGs and further device titrations were then performed at 2, 6, and 12 months after implantation to allow additional device optimization. Throughout the study period, participants were monitored for any adverse events. Weekly use questionnaires were completed and corroborated with total hours of use and mean use per week calculations automatically registered by the device itself at the time of device checks before each PSG. Mean nightly use was calculated by dividing the mean use per week recorded by the device by 7. All PSGs were scored using American Academy of Sleep Medicine (AASM) pediatric standards. All sleep studies and device titrations performed after implantation were conducted at our institution and interpreted, using the AASM criteria, by 1 of 2 board-certified sleep medicine specialists (D.K., T.B.K.).
In addition to safety and efficacy data, QOL data were obtained as a secondary outcome measure. The OSA-18 survey, which is a valid and reliable discriminative QOL instrument in children with sleep-disordered breathing, was used to assess QOL at baseline and at 2, 6, and 12 months after implantation. At most recent follow-up, a change score was calculated by subtracting the mean survey score from the mean score at baseline. One patient, patient 3, was excluded from follow-up analysis because only 1 of 18 questions was filled out at follow-up. Data from other surveys with 7-point response scales suggest that change scores of less than 0.5 represent trivial change, 0.5 to 0.9 indicate a small change, 1.0 to 1.4 demonstrate a moderate change, and 1.5 or greater indicate a large change.
Results
Preliminary results of the first 6 patients to receive hypoglossal nerve stimulator implantation as part of this pilot study are presented here. Five-month follow-up results of the first implant recipient have been reported previously.
Six patients, 4 male and 2 female, with residual OSA after T&A, age 12 to 18 years, were enrolled. All 6 patients were either unable to tolerate a CPAP trial (n = 2) or their CPAP therapy failed as a result of intolerance of associated equipment or sinonasal symptoms related to therapy (n = 4). One patient had a long-standing tracheotomy. Patient characteristics, including baseline PSG measurements, are included in Table 1. Three patients underwent DISE on the same date as implantation due to travel from a distance and/or parent request that the patient only be sedated and undergo anesthesia once given the added risks of anesthesia in the DS population; these deviations from protocol were approved by the institutional review board. Patterns of obstruction on DISE are presented in Table 2; none of the patients demonstrated circumferential collapse at the level of the velopharynx, and therefore all were candidates for implantation.
Table 1. Patient Characteristics and Baseline Polysomnogram Findings.
| Patient No. | Sex | Age, y | BMI | Baseline, Events/h | |
|---|---|---|---|---|---|
| AHI | CAI | ||||
| 1 | M | 14 | 24.6 | 48.5a | 2.4 |
| 2 | M | 15 | 26.1 | 17.1b | 0.8b |
| 3 | M | 13 | 19.2 | 30.7 | 0.0 |
| 4 | F | 12 | 20.3 | 22.7 | 4.7 |
| 5 | M | 17 | 28.8 | 13.9 | 2.9 |
| 6 | F | 18 | 25.8 | 25.6b | 6.3b |
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; CAI, central apnea index.
Measured with tracheostomy tube capped.
Values obtained from therapeutic portion of a split-night polysomnogram. The remainder of the patients underwent full-night studies for baseline value.
Table 2. Patterns of Obstruction Observed During Drug-Induced Sleep Endoscopy.
| Patient No. | Velopharynx | Oropharynx | Tongue Base | Hypopharynx/ Epiglottis |
|---|---|---|---|---|
| 1 | Complete AP | None | Complete AP | Complete AP |
| 2 | Partial AP | Partial LL | Complete AP | Complete AP |
| 3 | Partial AP | Partial AP | Complete AP | Partial AP |
| 4 | None | None | Complete AP | None |
| 5 | None | Partial AP | Complete AP | None |
| 6 | Partial AP | Partial AP | None | None |
Abbreviations: AP, anterior posterior; LL, laterolateral.
All patients underwent hypoglossal nerve stimulator implantation without intraoperative complications. All patients received 24 hours of perioperative antibiotics. All patients were hospitalized overnight for observation, and pain was well controlled using acetaminophen; use of narcotics after initial recovery in the postanesthesia care unit was minimized. All patients were discharged on postoperative day 1.
Two patients experienced adverse events in the perioperative period necessitating readmission. Patient 2 was rehospitalized the morning of postoperative day 2 with irritation, and possibly mild cellulitis, of his upper chest incision; this improved with antibiotic administration and he was discharged on postoperative day 4 to complete a course of oral antibiotics. He remained afebrile. Patient 3 was readmitted on postoperative day 3 due to poor pain control and discomfort, as well as purulent nasal discharge in the setting of known sinusitis; he was admitted for narcotic administration under direct monitoring and antibiotics, did not have adverse respiratory events, and was discharged home the following morning with narcotic medication to be used as needed and to complete a course of oral antibiotics.
All patients underwent activation 1 month after implantation. All patients tolerated stimulation and initial titration without discomfort and were discharged to use the device nightly and become acclimated to stimulation. The goal of initial activation and titration was not to optimize therapy, however, due to concerns that the children would not necessarily tolerate therapeutic levels of stimulation initially. Patient 4 demonstrated emergence of severe central apnea consistent with postobstructive hypoventilation syndrome, which has been described previously in children with severe OSA after T&A or with the initiation of CPAP therapy. She was admitted for 24-hour observation and continued therapy with the use of nocturnal supplemental oxygen. She was discharged home the following day with nocturnal oxygen and continuous oxygen saturation monitoring until respiratory center recalibration, and she continued to use therapy nightly. Her central apnea had resolved by her next sleep study, which was performed 3 months later, and she was weaned off supplemental oxygen.
All 6 patients demonstrated improvement in their airway obstruction with stimulation during their first PSG immediately following device activation, although further titration was needed in subsequent PSGs to optimize therapy (Table 3). At 6-month (n = 1) and 1-year follow-up (n = 5), all patients demonstrated persistent improvement in their AHI in response to therapy, with a 56% to 85% reduction in AHI compared with their preoperative baseline. At follow-up, whereas OSA persisted in all patients, it was no longer severe (AHI > 10 events/h); 4 patients demonstrated mild OSA (AHI ≤ 5 events/h), and 2 demonstrated moderate OSA (5 < AHI ≤ 10 events/h). At the time of most recent follow-up, all patients were using therapy nightly, with a mean duration of 5.6 to 10.0 h/night (Table 3).
Table 3. Polysomnogram Results Before and After Implantation.
| Patient No. | Preimplantation AHI, Events/h | Follow-up, mo | Stimulator Parameters, V | Postimplantation AHI, Events/h | Device Use, Mean, h/Night |
|---|---|---|---|---|---|
| 1 | 48.5a | 12 | 1.7-1.9 | 7.4b | 9.6 |
| 2 | 17.1 | 12 | 1.9 | 2.7 | 10.0 |
| 3 | 30.7 | 12 | 1.5 | 4.6 | 9.3 |
| 4 | 22.7 | 12 | 1.5 | 4.7 | 5.6 |
| 5 | 13.9 | 6 | 1.5-1.7 | 6.1c | 9.0 |
| 6 | 25.6 | 12 | 1.9-2.3 | 4.7d | 9.4 |
Abbreviation: AHI, apnea hypopnea index.
Measured with tracheostomy tube capped.
Patient 1: overall AHI, 7.4 events/h at 1.7-1.9V; AHI, 5.0 events/h at 1.9V (90% reduction compared with baseline).
Patient 5: overall AHI, 6.1 events/h at 1.5-1.7V; AHI, 5.4 events/h at 1.5V.
Patient 6: overall AHI, 4.7 events/h at 1.9-2.3V; AHI, 1.5 events/h at 2.3V.
Patient 1 was decannulated 4 months after implantation. Patients 2 and 3, who had previously been poorly tolerant of CPAP, were able to discontinue CPAP use. Prior to implantation, 3 patients (patients 1, 2, and 6) had no rapid eye movement sleep during baseline PSG recording, likely secondary to repeated arousals in the setting of severe upper airway obstruction with frequent respiratory events. However, each of these patients demonstrated emergence of rapid eye movement sleep with device use (20%, 21%, and 22% of total sleep time, for patients 1, 2, and 6, respectively), representing a more normal sleep pattern.
For the 5 patients with completed OSA-18 questionnaires at follow-up, all patients demonstrated improvement in their QOL. There was a large improvement (change score ≥1.5) in sleep disturbance, caregiver concerns, and the mean OSA-18 score, and a moderate improvement (1.0 ≤ change score ≤ 1.4) in daytime problems associated with OSA (Table 4).
Table 4. Baseline and Follow-up Domain Scores for the Obstructive Sleep Apnea–18 (OSA-18) Survey (n = 5).
| OSA-18 Domain | Domain Content Items | Change Score, Mean (SD), Range | Change Degreea |
|---|---|---|---|
| Sleep disturbance | Loud snoring; breath holding or pauses in breathing; choking or gasping; fragmented sleep | 1.9 (1.4), −0.5 to 3.0 | Large |
| Physical suffering | Mouth breathing; frequent colds or upper respiratory infections; rhinorrhea; dysphagia | 0.4 (0.7), −0.8 to 1.0 | Trivial |
| Emotional distress | Mood swings or temper tantrums; aggressive or hyperactive behavior; discipline problems | 0.9 (1.3), −0.7 to 2.7 | Small |
| Daytime problems | Excessive drowsiness or sleepiness; poor attention span; difficulty awakening | 1.4 (1.0), 0.3 to 1.5 | Moderate |
| Caregiver concerns | Caregiver worried over child health; concerned not getting enough air; missed activities; frustration | 2.2 (0.9), 1 to 3.3 | Large |
| Overall survey score | Mean score for all 18 items | 1.5 (0.6), 0.9 to 2.3b | Large |
Less than 0.5 indicates trivial change; 0.5 to 0.9, small change; 1.0 to 1.4, moderate change; 1.5 or greater, large change.
Mean score median at baseline and follow-up, 3 and 1.7, respectively.
Discussion
Here we present preliminary results of, to our knowledge, the first 6 pediatric hypoglossal nerve stimulator recipients ever implanted. In carefully selected children and adolescents with DS, surgical implantation and use were well tolerated. After appropriate device titration, the nerve stimulator was effective in relieving upper airway obstruction with a greater than 50% reduction in AHI in all patients. In patients reliant on tracheotomy and CPAP, nerve stimulator therapy was so successful that these therapies could be discontinued after initial titration sessions. Patients not only exhibited an improvement in their AHI but also showed clinically significant improvement in their QOL based on validated QOL instruments.
Based on parent report and corroboration from device interrogation at follow-up visits, patients were using the stimulator for a mean duration of 5.6 to 10.0 h/night (group mean, 8.8 h/night). Adherence to therapy was significantly higher than mean adherence to CPAP therapy in adult patients, which has been reported previously to be as low as 3.3 h/night. Despite the effectiveness of CPAP when used properly, lack of adherence to therapy may be a contributing factor in recent studies demonstrating no reduction of cardiovascular event risk with CPAP therapy in adult patients with moderate to severe sleep apnea and cardiovascular disease. Further study is needed to determine whether hypoglossal stimulation therapy reduces cardiovascular risk in both pediatric and adult patients with OSA. However, we demonstrate that adherence to therapy, which may be an important factor in the prevention of long-term sequelae, was not problematic in our patient population.
Limitations
In our patients who have completed the 1-year pilot study, voltage settings were relatively stable; however, further long-term study is needed to determine whether effectiveness, particularly through other measures of gas exchange, and stimulation parameters remain stable over a longer period in this patient population. Studies of stimulation in adult patients have shown a persistent response over 36 months. Hypoglossal nerve stimulation represents a potential therapeutic option for children with DS and refractory OSA after T&A who are unable to tolerate noninvasive interventions. For this pilot study, we chose older children and adolescents for implantation due to concern about the size of the impulse generator device, as well as the potential for growth during puberty to displace the device’s stimulation and sensing leads. In addition, the battery of the impulse generator will need to be replaced approximately every 10 years due to limitations in battery capacity, which raises additional safety concerns. The ideal age for implantation in the pediatric population has not been established. Additionally, it remains unclear whether hypoglossal nerve stimulation may represent a treatment option for pediatric patients without DS who demonstrate persistent OSA after T&A. The risks and benefits of implantation, as well as long-term follow-up, will need to be considered as more data are collected on initial pediatric implant recipients.
The patients and families included in this pilot study represent a unique group. Patients were high functioning, able to communicate well with investigators and their families. Patient families were also motivated to proceed with surgery and to help facilitate adherence to therapy. This could limit applicability of our results to other adolescents and young adults with DS who may be less communicative and cooperative, and whose families may not be as involved in their care.
Conclusions
Adolescents and young adults with DS are at increased risk for refractory severe OSA. We demonstrate that therapy was well tolerated and effective, both in improving QOL and in reducing AHI, in our patient population. Hypoglossal nerve stimulator implantation represents a potential therapeutic option, but further research is needed to optimize patient selection and better assess long-term efficacy.
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