Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea.

Importance: Patients with Down syndrome have a high incidence of persistent obstructive sleep apnea (OSA) and limited treatment options. Upper airway hypoglossal stimulation has been shown to be effective for adults with OSA but has not yet been evaluated for pediatric populations. Objective: To evaluate the safety and effectiveness of upper airway stimulation for adolescent patients with Down syndrome and severe OSA. Design, Setting, and Participants: This prospective single-group multicenter cohort study with 1-year follow-up was conducted between April 1, 2015, and July 31, 2021, among a referred sample of 42 consecutive adolescent patients with Down syndrome and persistent severe OSA after adenotonsillectomy. Intervention: Upper airway stimulation. Main Outcomes and Measures: The prespecified primary outcomes were safety and the change in apnea-hypopnea index (AHI) from baseline to 12 months postoperatively. Polysomnographic and quality of life outcomes were assessed at 1, 2, 6, and 12 months postoperatively. Results: Among the 42 patients (28 male patients [66.7%]; mean [SD] age, 15.1 [3.0] years), there was a mean (SD) decrease in AHI of 12.9 (13.2) events/h (95% CI, -17.0 to -8.7 events/h). With the use of a therapy response definition of a 50% decrease in AHI, the 12-month response rate was 65.9% (27 of 41), and 73.2% of patients (30 of 41) had a 12-month AHI of less than 10 events/h. The most common complication was temporary tongue or oral discomfort, which occurred in 5 patients (11.9%). The reoperation rate was 4.8% (n = 2). The mean (SD) improvement in the OSA-18 total score was 34.8 (20.3) (95% CI, -42.1 to -27.5), and the mean (SD) improvement in the Epworth Sleepiness Scale score was 5.1 (6.9) (95% CI, -7.4 to -2.8). The mean (SD) duration of nightly therapy was 9.0 (1.8) hours, with 40 patients (95.2%) using the device at least 4 hours a night. Conclusions and Relevance: Upper airway stimulation was able to be safely performed for 42 adolescents who had Down syndrome and persistent severe OSA after adenotonsillectomy with positive airway pressure intolerance. There was an acceptable adverse event profile with high rates of therapy response and quality of life improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT02344108.

Long-term stability of hypoglossal nerve stimulation for the treatment of obstructive sleep apnea in children with Down syndrome.

IMPORTANCE: Obstructive sleep apnea (OSA) occurs in 55-97% of people with Down syndrome (DS). Even after adenotonsillectomy, residual OSA often persists into adulthood due, in part, to tongue base collapse. Implantable hypoglossal nerve stimulators are being investigated in children and young adults with DS and persistent, moderate to severe OSA. However, the long-term necessity for such an intervention-especially as patients mature and voltage adjustment becomes warranted-has not been previously reported in the pediatric DS population. OBJECTIVE: To assess the long-term need for implantable hypoglossal nerve stimulators and the necessity for voltage adjustment in children and young adults with Down syndrome. DESIGN: This is a case series from an ongoing clinical trial assessing safety and efficacy of hypoglossal nerve stimulation among 42 children and young adults with DS and persistent OSA, despite adenotonsillectomy and trialed positive airway pressure (PAP) therapy. We focus here on the first 4 participants who have undergone implantation by age 13 and have completed at least 44 months of follow-up. PARTICIPANTS: 4 participants (2 male, 2 female; ages 10-13 years) with DS and persistent, severe OSA (AHI > 10 events/h) underwent hypoglossal nerve stimulator implantation and were followed for 44-58 months. SETTING: Participants completed in-lab sleep studies at baseline (before implantation), 1 year postoperatively, and 44-58 months postoperatively. During their most recent follow-up, 2 participants completed split-night sleep studies in which assessment was done with the device both on and off. INTERVENTIONS: Hypoglossal nerve stimulator implantation. MAIN OUTCOMES AND MEASURES: Stability in titrated and untitrated OSA as measured by the apnea-hypopnea index (AHI); growth measures including BMI; and quality of life as measured by the OSA-18 questionnaire. RESULTS: Compared to baseline, all 4 participants maintained reductions of at least 50% in AHI over the course of follow-up. At recent follow-up, two participants had persistent, moderate OSA despite stimulation therapy. The other two participants achieved 100% reductions in AHI with stimulation therapy; when they underwent split-night sleep studies, the severe OSA persisted with the device turned off. Improvement in OSA-18 quality of life scores was observed in three of the four participants. CONCLUSION: and Relevance: Hypoglossal nerve stimulation continues to effectively control OSA in children with DS as they mature, while their underlying untitrated OSA appears to persist into adulthood. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT2344108.

Redefining Success by Focusing on Failures After Pediatric Hypoglossal Stimulation in Down Syndrome.

OBJECTIVES/HYPOTHESIS: Patients with Down syndrome have a high incidence of obstructive sleep apnea (OSA) and limited treatment options. Hypoglossal stimulation has shown efficacy but has not yet been approved for pediatric populations. Our objective is to characterize the therapy response of adolescent patients with down syndrome and severe OSA who underwent hypoglossal stimulation. STUDY DESIGN: Prospective longitudinal trial. METHODS: We are conducting a multicenter single-arm trial of hypoglossal stimulation for adolescent patients with Down syndrome and severe OSA. Interim analysis was performed to compare objective sleep and quality of life outcomes at 12 months postoperatively for the first 20 patients. RESULTS: The mean age was 15.5 and baseline AHI 24.2. Of the 20 patients, two patients (10.0%) had an AHI under 1.5 at 12 months; nine patients of 20 (45.0%) under five; and 15 patients of 20 (75.0%) under 10. The mean decrease in AHI was 15.1 (P < .001). Patients with postoperative AHI over five had an average baseline OSA-18 survey score of 3.5 with an average improvement of 1.7 (P = .002); in addition, six of these patients had a relative decrease of apneas compared to hypopneas and seven had an improvement in percentage of time with oxygen saturation below 90%. CONCLUSIONS: Patients with persistently elevated AHI 12 months after hypoglossal implantation experienced improvement in polysomnographic and quality of life outcomes. These results suggest the need for a closer look at physiologic markers for success beyond reporting AHI as the gold standard. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1663-1669, 2021.

Distribution of ERK1/2 and ERK3 during normal rat fetal lung development.

The extracellular regulated kinases-1 and -2 (ERK1/2) are well-characterized mitogen-activated protein kinases (MAPK) that play critical roles in proliferation and differentiation, whereas the function(s) of MAPK ERK3 are currently unknown. To understand better the roles of these kinases in development, the temporal distribution of ERK1, -2, and -3 proteins were investigated in multiple tissues. The ERK3 protein, in contrast to ERK1/2 varied both between and within individual organs over time. To characterize this variability in greater detail, the temporal and spatial distributions of activated ERK1/2 and ERK3 during rat fetal lung development were investigated. The diphosphorylated (activated) forms of ERK1/2 (dp-ERK1/2), ERK3, and its phosphorylated form (P-ERK3) decreased from embryonic day 17 (E17) through E21 while both ERK1 and ERK2 total proteins remained unchanged, indicating that ERK1/2 and ERK3 proteins are expressed independently during fetal lung development. In addition, characterization of the distribution of these proteins by fluorescent immunohistochemistry indicated that phosphorylated ERK1/2 and total ERK1/2 were distributed throughout multiple cell types, with the phosphorylated ERK1/2 colocalizing with prophase mitotic cells. In contrast, ERK3 was restricted to the distal lung epithelium during the pseudoglandular phase (E17) but shifted to the proximal airways, particularly Clara cells during the saccular stage (E21). The P-ERK3 colocalized with the mitotic marker P-histone H3 in fetal lung and in NIH3T3 and HeLa cells, implicating a potential role for P-ERK3 in mitosis. Thus, expression of ERK1/2 and ERK3 and their phosphorylated forms are expressed independently and are temporally and spatially localized during fetal lung morphogenesis. These observations will facilitate detailed functional analysis of these kinases to assess their roles in pulmonary development and diseases.

Lactic acid is a potential virulence factor for group B Streptococcus.

Group B Streptococcus (GBS) is a Gram-positive bacterium that causes sepsis and meningitis in neonates and infants. Although several GBS-associated virulence factors have been described, the mechanisms of GBS invasive disease are not well understood. To characterize additional virulence factors, a novel in vitro infection assay was developed using rat fetal lung explants. However, application of GBS to the system induced rapid lung tissue destruction associated with increased media acidity. Since lactic acid produced by other streptococci is an important virulence factor, we hypothesized that lactic acid contributed to the virulence of GBS. Spent growth media and neutralized-spent media were applied to explants and results indicated that neutralization of the media completely protected the tissue from degradation. These results were verified using multiple viability assays and with transformed cell lines. Furthermore, comparable spent media from Escherichia coli did not induce tissue cytotoxicity, suggesting that GBS produces organic acids in excess of other potential bacterial pathogens. Analysis of the spent media indicated that l-lactate levels reached approximately 70 mM, indicating that lactic acid is a major constituent of the metabolic acid produced by GBS. Treatment of explants with lactic acid alone produced dose-dependent tissue degradation, indicating that lactic acid is independently sufficient to induce target-tissue cytotoxicity. Finally, both spent media and 23.6 mM lactic acid produced dramatic tissue autofluorescence; the basis for this is currently unknown. These studies demonstrate that GBS-produced lactic acid is a potential virulence factor and may contribute to GBS invasive disease.