Advances in Sleep-Disordered Breathing in Children.

Pediatric sleep-disordered breathing disorders are a group of common conditions, from habitual snoring to obstructive sleep apnea (OSA) syndrome, affecting a significant proportion of children. The present article summarizes the current knowledge on diagnosis and treatment of pediatric OSA focusing on therapeutic and surgical advancements in the field in recent years. Advancements in OSA such as biomarkers, improving continuous pressure therapy adherence, novel pharmacotherapies, and advanced surgeries are discussed.

Completion of postoperative polysomnography for children with severe obstructive sleep apnea: A quality improvement project.

Objective: Pediatric patients with severe obstructive sleep apnea (OSA) are at risk for residual OSA following tonsillectomy with/without adenoidectomy (T ± A). We initiated a quality improvement (QI) project to increase the percentage of postoperative (postop) polysomnography (PSG) completion to identify residual OSA. Methods: This is a prospective QI project carried out at a tertiary pediatric academic hospital. Children ≤18 years of age who underwent T ± A for severe OSA were included. Our Specific, Measurable, Attainable, Relevant, and Time-based (SMART) aim was to increase the percentage of completed postop PSGs in this cohort from a baseline of 70% to95% by May 31, 2021. We focused on patient education and leveraged both clinical decision support and reporting functionalities of the electronic medical record for project implementation. Results: During the pre-intervention period between January 1, 2019 to June 30, 2020, 472 patients met the inclusion criteria with an average age of 8.6 years (SD 4.6). The rate of postop PSG completion was 69.7% (SD 11.4%) with an average time of 99 days (SD 66) between surgery and the postop PSG. A shift was observed starting in September 2020, and the PSG completion rate improved to 94.9% by September 30, 2021. Post-intervention, there were 178 patients with an average age of 9.3 years (SD 4.9). The average time between surgery and the postop PSG was significantly reduced to 57 days (SD 16; p < .001). Conclusions: Through a multidisciplinary approach, we successfully completed our SMART aim. With the establishment of QI infrastructure, our goal is to deliver better care in a sustainable fashion using QI methodology.

Management and outcome of extreme pediatric obstructive sleep apnea.

OBJECTIVES: Classify post-adenotonsillectomy (AT) respiratory support, identify variables that predict these interventions, and evaluate outcomes in children with extreme obstructive sleep apnea (OSA). METHODS: Retrospective chart analysis was performed on patients found to have apnea/hypopnea index (AHI) > 100 events/h. Patients with chronic diseases other than obesity were excluded. RESULTS: Forty-one subjects were studied, average age of 11.4 ± 4.3 years, majority (73.1%) were Hispanic, with a mean total AHI (TAHI) of 128.1 ± 22.9/h. Twenty-eight (68.3%) patients underwent AT. Lower age (P < 0.001), lower BMI Z-score (P < 0.01), higher OAHI (P < 0.05) were associated with having surgery. Eleven out of 28 (39.3%) surgical patients required respiratory support (oxygen or positive airway pressure) postoperatively. Longer % total sleep time SpO2 <90% during PSG (P < 0.05) and lower SpO2 nadir (P < 0.05) were associated with requiring airway support. No patients experienced mortality, reintubation, or hospital readmission following AT, with majority (71.4%) discharged 1 day post-operatively. Eleven (57.9%) of the 19 patients who had a postoperative PSG had residual OSA, defined as AHI >5 events/h, but there was a significant improvement in TAHI (P < 0.01). CONCLUSION: Our findings confirm the need for postoperative observation in a controlled setting for patients with extreme OSA undergoing AT. Although at higher risk of needing respiratory support, those patients undergoing AT for extreme OSA did not require re-intubation post-operatively or suffer serious harm. Barring contraindications to AT, surgery may still be a first-line therapy for some children with extreme OSA.

Multidisciplinary clinic for care of children with complex obstructive sleep apnea.

OBJECTIVE: While adenotonsillectomy (AT) remains first line therapy for pediatric obstructive sleep apnea (OSA), management of children who are not candidates for AT or who have residual OSA post AT varies and spans across multiple specialties. We aim to report our experience in managing this population through a multidisciplinary sleep clinic composed of specialists in pediatric dentistry, otolaryngology, plastic surgery, and pulmonary/sleep medicine. STUDY DESIGN: Retrospective chart review. METHOD: The medical records of children attending our complex sleep apnea clinic were reviewed. Data pertaining to demographics, underlying diagnoses, prior evaluation and treatment, recommendations, and initial therapy were collected. RESULT: Two-hundred and thirty patients (mean age 10.7 ± 5.1 years, 62.2% male) were assessed. Underlying conditions included Trisomy 21 (n = 65, 28.2%), other genetic syndromes (n = 37, 16.1%), obesity in an otherwise typically developing child (n = 36, 15.2%), cerebral palsy (n = 27, 11.7%), and craniofacial syndromes (n = 7, 3.0%). Mean obstructive apnea hypopnea index (OAHI) was 14.2 events/hour at first clinic visit, and the majority of children had previously undergone at least one upper airway surgery (n = 168, 73.0%), primarily adenotonsillectomy. Recommended initial treatment plans included positive airway pressure (PAP) therapy (n = 108, 47.0%), surgery (n = 75, 32.6%), allergy management (n = 52, 22.6%), and/or weight loss (n = 34, 14.8%). Patients prescribed PAP therapy with follow up data were found to be adherent 43.9% of the time. Surgical patients with post-operative polysomnography had pre-operative OAHI 15.6 ± SD13.4 decrease to 10.7 ± 14.2 events/hour (p = 0.61). CONCLUSION: Genetic conditions and obesity were the most common underlying diagnoses cared for in the complex sleep apnea clinic. Patients presented with severe OSA, most having already had upper airway surgery. Management plans were frequently adjusted, and we observed improvement in SDB in a sub-segment of patients, suggesting benefit to a coordinated, multi-disciplinary approach.

Findings of routine nocturnal polysomnography in children with Down syndrome: a retrospective cohort study.

STUDY OBJECTIVE: Children with Down syndrome (DS) are at risk for sleep disorders including; obstructive sleep apnea (OSA). Although OSA is diagnosed by polysomnography (PSG), the practicality of PSG in DS is questionable. Further, OSA treatment efficacy in DS is largely unknown given the challenges of PSG. Our aims were to review (i) the feasibility of PSG, and (ii) the efficacy (improvement in obstructive apnea hypopnea index (OAHI)) of OSA treatment using follow-up PSG in DS. METHODS: Retrospective review of patients aged <21 years with DS who underwent PSG from October 2016 to June 2019. Successful PSG was determined using total sleep time (TST). PSG following treatment with adenotonsillectomy (AT) or positive airway pressure (PAP) was evaluated and compared to pre-treatment. RESULTS: Among 248 patients with DS, only 11(4.4%) had unsuccessful PSG (TST<1h). Of the 237 successful studies (age: 7.9 ± 0.3y), average TST and sleep efficiency was 5.6 ± 0.1h and 79.5 ± 1.3%. 41 had post-AT PSG and 11(27%) achieved OSA cure (OAHI<2) with all demonstrating improved SE (p = 0.01) and OAHI (p = 0.0003). Multivariate analysis revealed only age was predictive (p = 0.003) of residual OSA post-AT. Of 24 children who underwent PAP titration, 20(83%) tolerated titration with improved OAHI (p = 0.01), however, no significant improvements in SE were observed. CONCLUSIONS: In a large cohort of DS children, PSG was well tolerated. Following AT or PAP therapy, post treatment PSG confirmed efficacy, although residual OSA was identified. PSG is thus both feasible and useful in identifying OSA, OSA treatment response and should guide in decision making in children with DS.

Sleep disordered breathing in children with trisomy 13 and trisomy 18.

PURPOSE: While the prevalence of obstructive sleep apnea (OSA) is well documented in trisomy 21, there has been little published about the incidence in trisomy 13 (T13) and trisomy 18 (T18). Trisomies 13, 18, and 21 have overlapping clinical features that make patients prone to OSA. Because the literature regarding OSA in T13 and T18 children is limited, we performed a retrospective chart review to investigate the characteristics of these patients. METHODS: We reviewed the medical records of children with T13 or T18 seen at seen at a single urban tertiary children's hospital for sleep disordered breathing from 1/1/10 to 5/1/18. Candidates were selected based on ICD-9 diagnosis and procedural codes. RESULTS: We identified 21 T18 patients that had documented symptoms of SDB, of which 3 were diagnosed with OSA, 11 had clinical SDB, and 7 had snoring. Of the T13 patients, 10 had documented symptoms of SDB, of which 1 patient was diagnosed with OSA, 7 with clinical SDB, and 2 with snoring. In both T13 and T18 patients, anatomical features included micrognathia/mandibular hypoplasia, small mouth/small airway, midface hypoplasia, abnormal/difficult airway, glossoptosis, hypotonia, and GERD. Endoscopic findings included laryngomalacia and/or tracheomalacia, adenoid and lingual tonsil hypertrophy, and inferior turbinate hypertrophy. Surgical interventions performed in T13 and T18 patients included adenoidectomy, lingual tonsillectomy, and tracheostomy. Of the 32 T13 and T18 patients, 15 had to be intubated for respiratory insufficiency. CONCLUSION: The results of our study suggest that T13 and T18 patients are at increased risk for OSA due to common features found in this population. These findings indicate a need for otolaryngologist intervention to increase both survival and quality of life in this population.

Polysomnography Parameters Assessing Gas Exchange Best Predict Postoperative Respiratory Complications Following Adenotonsillectomy in Children With Severe OSA.

STUDY OBJECTIVES: Adenotonsillectomy (AT) is the treatment of choice for obstructive sleep apnea (OSA) in children with adenotonsillar hypertrophy. Severe OSA, identified by the apnea-hypopnea index (AHI), is a risk factor for surgical complications and AHI thresholds are used by surgeons to decide elective postoperative hospital admissions. The objective of this study was to identify the prevalence of surgical complications of AT in children with severe OSA and determine their association with specific parameters of polysomnography (PSG). METHODS: Retrospective evaluation of respiratory and nonrespiratory complications in children undergoing AT for severe OSA was performed. Events were then compared to several individual PSG indices. PSG indices included classic parameters such as AHI, and obstructive apnea indexes (OAI) as well as gas exchange parameters including the oxygen desaturation index (ODI), lowest oxyhemoglobin saturation (lowest SpO2), peak end-tidal CO2 (peak ETCO2), the percentage of the total sleep time (%TST) with ETCO2 > 50 mmHg (%TST ETCO2 > 50 mmHg) and oxygen saturation < 90% (%TST O2 < 90%). RESULTS: A total of 158 children were identified with severe OSA. Major respiratory complications occurred in 21.5% and were only associated with the ODI (P = .014), lowest SpO2 (P = .001) and %TST O2 < 90% (P < .001). Minor respiratory complications occurred in 19.6% and these were not associated with any PSG parameters. Major nonrespiratory complications occurred in 4.4% and also were not associated with any PSG parameters; however, minor nonrespiratory complications occurring in 37.3%, and were associated with %TST O2 < 90% (P < 0.001). CONCLUSIONS: PSG measures of gas exchange are strongly associated with postoperative complications of AT and are better suited for postoperative planning than classic indices such as AHI. CITATION: Molero-Ramirez H, Tamae Kakazu M, Baroody F, Bhattacharjee R. Polysomnography parameters assessing gas exchange best predict postoperative respiratory complications following adenotonsillectomy in children with severe OSA. J Clin Sleep Med. 2019;15(9):1251-1259.

Exosomal Cargo Properties, Endothelial Function and Treatment of Obesity Hypoventilation Syndrome: A Proof of Concept Study.

STUDY OBJECTIVES: Longitudinal studies support the usage of positive airway pressure (PAP) therapy in treating obstructive sleep apnea (OSA) to improve cardiovascular disease. However, the anticipated benefit is not ubiquitous. In this study, we elucidate whether PAP therapy leads to immediate improvements on endothelial function, a subclinical marker of cardiovascular status, by examining the effect of circulating exosomes, isolated from patients before and after PAP therapy, on naive endothelial cells. METHODS: We isolated plasma-derived circulating exosomes from 12 patients with severe OSA and obesity hypoventilation syndrome (OHS) before and after 6 weeks of PAP therapy, and examined their effect on cultured endothelial cells using several in vitro reporter assays. RESULTS: We found that circulating exosomes contributed to the induction and propagation of OSA/OHS-related endothelial dysfunction (ie, increased permeability and disruption of tight junctions along with increased adhesion molecule expression, and reduced endothelial nitric oxide synthase expression), and promoted increased monocyte adherence. Further, when comparing exosomes isolated before and after PAP therapy, the disturbances in endothelial cell function were attenuated with treatment, including an overall cumulative decrease in endothelial permeability in all 12 subjects by 10.8% (P = .035), as well as detection of a subset of 4 differentially expressed exosomal miRNAs, even in the absence of parallel changes in systemic blood pressure or metabolic function. CONCLUSIONS: Circulating exosomes facilitate important intercellular signals that modify endothelial phenotype, and thus emerge as potential fundamental contributors in the context of OSA/OHS-related endothelial dysfunction. Exosomes may not only provide candidate biomarkers, but are also a likely and plausible mechanism toward OSA/OHS-induced cardiovascular disease. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Title: AVAPS-AE Efficacy Study, URL: https://clinicaltrials.gov/ct2/show/NCT01368614, Identifier: NCT01368614.

Circulating Plasma Extracellular Microvesicle MicroRNA Cargo and Endothelial Dysfunction in Children with Obstructive Sleep Apnea.

RATIONALE: Obese children are at increased risk for developing obstructive sleep apnea (OSA), and both of these conditions are associated with an increased risk for endothelial dysfunction (ED) in children, an early risk factor for atherosclerosis and cardiovascular disease. Although weight loss and treatment of OSA by adenotonsillectomy improve endothelial function, not every obese child or child with OSA develops ED. Exosomes are circulating extracellular vesicles containing functional mRNA and microRNA (miRNA) that can be delivered to other cells, such as endothelial cells. OBJECTIVES: To investigate whether circulating exosomal miRNAs of children with OSA differentiate based on endothelial functional status. METHODS: Obese children (body mass index z score >1.65) and nonobese children were recruited and underwent polysomnographic testing (PSG), and fasting endothelial function measurements and blood draws in the morning after PSG. Plasma exosomes were isolated from all subjects. Isolated exosomes were then incubated with confluent endothelial cell monolayer cultures. Electric cell-substrate impedance sensing systems were used to determine the ability of exosomes to disrupt the intercellular barrier formed by confluent endothelial cells. In addition, immunofluorescent assessments of zonula occludens-1 tight junction protein cellular distribution were conducted to examine endothelial barrier dysfunction. miRNA and mRNA arrays were also applied to exosomes and endothelial cells, and miRNA inhibitors and mimics were transfected for mechanistic assays. MEASUREMENTS AND MAIN RESULTS: Plasma exosomes isolated from either obese children or nonobese children with OSA were primarily derived from endothelial cell sources and recapitulated ED, or its absence, in naive human endothelial cells and also in vivo when injected into mice. Microarrays identified a restricted signature of exosomal miRNAs that readily distinguished ED from normal endothelial function. Among the miRNAs, expression of exosomal miRNA-630 was reduced in children with ED and normalized after therapy along with restoration of endothelial function. Conversely, transfection of exosomes from subjects without ED with an miRNA-630 inhibitor induces the ED functional phenotype. Gene target discovery experiments further revealed that miRNA-630 regulates 416 gene targets in endothelial cells that include the Nrf2, AMP kinase, and tight junction pathways. CONCLUSIONS: These observations elucidate a novel role of exosomal miRNA-360 as a putative key mediator of vascular function and cardiovascular disease risk in children with underlying OSA and/or obesity, and identify therapeutic targets.

Impact of Adenotonsillectomy on Insulin Resistance and Lipoprotein Profile in Nonobese and Obese Children.

BACKGROUND: OSA associates with insulin resistance (IR), hyperglycemia, and dyslipidemia consistently in adults, but inconsistently in children. We set out to quantify the impact of OSA treatment upon obesity and metabolic outcomes and thus assess causality. METHODS: Sixty-nine children with OSA; mean age, 5.9 years (range, 3-12.6); 55% boys; and 68% nonobese (NOB) underwent baseline overnight polysomnography, anthropometric and metabolic measurements, adenotonsillectomy (T&A), and follow-up testing a mean 7.9 months (range, 2-20) later. RESULTS: Fifty-three children (77% of study cohort; 91% of obese children) had residual OSA (apnea-hypopnea index > 1 event/h) post-T&A. Fasting plasma insulin (FPI, 14.4 ± 9.4 → 12.6 ± 9.7 µIU/mL, P = .008), homeostasis model assessment-IR (3.05 ± 2.13 → 2.62 ± 2.22, P = .005), and high-density lipoprotein (HDL) (51.0 ± 12.9 → 56.5 ± 14.4 mg/dL, P = .007) improved despite increased BMI z score (1.43 ± 0.78 → 1.52 ± 0.62, P = .001); changes did not differ significantly between sexes or NOB and obese participants; however, post-T&A BMI z score rather than apnea-hypopnea index was the main predictor of levels of follow-up FPI, HDL, and other metabolic parameters. Higher baseline FPI and BMI-z predicted likelihood of residual OSA; conversely, on regression analysis, follow-up IR, HDL, and triglycerides were predicted by BMI z score, not residual OSA. CONCLUSIONS: T&A improved IR and HDL, and residual OSA is predicted by baseline FPI and BMI z score, indicating a causal relationship; however, following T&A, residual metabolic dysfunction related to underlying adiposity rather than remaining sleep-disordered breathing. Finally, T&A cured OSA in < 25% of all children and only 10% of obese children; post-T&A polysomnography is indicated to assess which children still require treatment.

C-reactive Protein as a Potential Biomarker of Residual Obstructive Sleep Apnea Following Adenotonsillectomy in Children.

STUDY OBJECTIVES: Adenotonsillectomy (AT) is first-line treatment for pediatric obstructive sleep apnea (OSA), with most children having improvements in polysomnography (PSG). However, many children have residual OSA following AT as determined through PSG. Identification of a biomarker of residual disease would be clinically meaningful to detect children at risk. We hypothesize serum high-sensitivity C-reactive protein (hsCRP), an inflammatory biomarker, is predictive of residual OSA following AT. METHODS: PSG was performed both preoperatively and postoperatively on children undergoing AT for the diagnosis of OSA. HsCRP serum concentrations were determined in all children pre-AT, and in most children post-AT. Resolution of OSA after AT was defined by a post-AT apnea-hypopnea index (AHI) < 1.5/h total sleep time (TST). Residual OSA was defined as a post-AT AHI > 5/h TST, which is considered clinically significant. RESULTS: AT significantly improved the AHI from 15.9 ± 16.4 to 4.1 ± 5.3/h TST in 182 children (P < 0.001). Of 182 children, residual OSA (post-AT AHI > 5) was seen in 46 children (25%). Among children who had hsCRP levels measured pre- and post-AT (n = 155), mean hsCRP levels pre-AT were 0.98 ± 1.91 mg/L and were significantly reduced post-AT (0.63 ± 2.24 mg/dL; P = 0.011). Stratification into post-AT AHI groups corresponding to < 1.5/h TST, 1.5/h TST < AHI < 5/h TST, and AHI > 5/h TST revealed post-AT hsCRP levels of 0.09 ± 0.12, 0.57 ± 2.28, and 1.49 ± 3.34 mg/L with statistical significance emerging comparing residual AHI > 5/h TST compared to post-AT AHI < 1.5/h TST (P = 0.006). Hierarchical multivariate modeling confirmed that pre-AT AHI and post-AT hsCRP levels were most significantly associated with residual OSA. CONCLUSIONS: Even though AT improves OSA in most children, residual OSA is frequent. Assessment of post-AT hsCRP levels emerges as a potentially useful biomarker predicting residual OSA.

Adenotonsillectomy Complications: A Meta-analysis.

BACKGROUND AND OBJECTIVE: Complications after adenotonsillectomy (AT) in children have been extensively studied, but differences between children with and without obstructive sleep apnea (OSA) have not been systematically reported. Our objective was to identify the most frequent complications after AT, and evaluate if differences between children with and without OSA exist. METHODS: Several electronic databases were searched. A partial gray literature search was undertaken by using Google Scholar. Experts were consulted to identify any missing publications. Studies assessing complications after AT in otherwise healthy children were included. One author collected the required information from the selected articles. A second author crosschecked the collected information and confirmed its accuracy. Most of the selected studies collected information from medical charts. RESULTS: A total of 1254 studies were initially identified. Only 23 articles remained after a 2-step selection process. The most frequent complication was respiratory compromise (9.4%), followed by secondary hemorrhage (2.6%). Four studies compared postoperative complications in children with and without OSA, and revealed that children with OSA have nearly 5 times more respiratory complications after AT than children without OSA (odds ratio = 4.90; 95% confidence interval: 2.38-10.10). In contrast, children with OSA are less likely to have postoperative bleeding when compared with children without OSA (odds ratio = 0.41; 95% confidence interval: 0.23-0.74). CONCLUSIONS: The most frequent early complications after AT are respiratory compromise and secondary hemorrhage. Based on the current limited evidence, children with OSA appear to have more respiratory complications. Conversely, hemorrhage appears to be more frequent in children without OSA.

Association of adenotonsillectomy with asthma outcomes in children: a longitudinal database analysis.

BACKGROUND: Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children. METHODS AND FINDINGS: Using the 2003-2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%-34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%-45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%-33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%-48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%-17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%-22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%-14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%-26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children. CONCLUSIONS: In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control. Please see later in the article for the Editors' Summary.

Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age.

RATIONALE: Apnea of prematurity is a common condition that is usually treated with caffeine, an adenosine receptor blocker that has powerful influences on the central nervous system. However, little is known about the long-term effects of caffeine on sleep in the developing brain. OBJECTIVES: We hypothesized that neonatal caffeine use resulted in long-term abnormalities in sleep architecture and breathing during sleep. METHODS: A total of 201 ex-preterm children aged 5-12 years who participated as neonates in a double-blind, randomized, controlled clinical trial of caffeine versus placebo underwent actigraphy, polysomnography, and parental sleep questionnaires. Coprimary outcomes were total sleep time on actigraphy and apnea-hypopnea index on polysomnography. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in primary outcomes between the caffeine group and the placebo (adjusted mean difference of -6.7 [95% confidence interval (CI) = -15.3 to 2.0 min]; P = 0.13 for actigraphic total sleep time; and adjusted rate ratio [caffeine/placebo] for apnea-hypopnea index of 0.89 [95% CI = 0.55-1.43]; P = 0.63). Polysomnographic total recording time and total sleep time were longer in the caffeine group, but there was no difference in sleep efficiency between groups. The percentage of children with obstructive sleep apnea (8.2% of caffeine group versus 11.0% of placebo; P = 0.22) or elevated periodic limb movements of sleep (17.5% in caffeine group versus 11% in placebo group) was high, but did not differ significantly between groups. CONCLUSIONS: Therapeutic neonatal caffeine administration has no long-term effects on sleep duration or sleep apnea during childhood. Ex-preterm infants, regardless of caffeine status, are at risk for obstructive sleep apnea and periodic limb movements in later childhood.

Antiinflammatory therapy outcomes for mild OSA in children.

BACKGROUND: OSA is highly prevalent in children and usually initially treated by adenotonsillectomy. Nonsurgical alternatives for mild OSA primarily consisting of antiinflammatory approaches have emerged, but their efficacy has not been extensively assessed. METHODS: A retrospective review of clinically and polysomnographically diagnosed patients with OSA treated between 2007 and 2012 was performed to identify otherwise healthy children ages 2 to 14 years who fulfilled the criteria for mild OSA and who were treated with a combination of intranasal corticosteroid and oral montelukast (OM) for 12 weeks (ICS + OM). A subset of children continued OM treatment for 6 to 12 months. RESULTS: A total of 3,071 children were diagnosed with OSA, of whom 836 fulfilled mild OSA criteria and 752 received ICS + OM. Overall, beneficial effects occurred in > 80% of the children, with nonadherence being documented in 61 children and adenotonsillectomy being ultimately performed in 12.3%. Follow-up polysomnography in a subset of 445 patients showed normalization of sleep findings in 62%, while 17.1% showed either no improvement or worsening of their OSA. Among the latter, older children (aged > 7 years; OR, 2.3; 95% CI, 1.43-4.13; P < .001) and obese children (BMI z-score > 1.65; OR: 6.3; 95% CI, 4.23-11.18; P < .000001) were significantly more likely to be nonresponders. CONCLUSIONS: A combination of ICS + OM as initial treatment of mild OSA appears to provide an effective alternative to adenotonsillectomy, particularly in younger and nonobese children. These results support implementation of multicenter randomized trials to more definitively establish the role of ICS + OM treatment in pediatric OSA.

Variants in C-reactive protein and IL-6 genes and susceptibility to obstructive sleep apnea in children: a candidate-gene association study in European American and Southeast European populations.

BACKGROUND: Preliminary evidence indicates that variants of the C-reactive protein (CRP) and IL-6 genes might be associated with the presence of obstructive sleep apnea (OSA) in childhood. Thus a candidate-gene association study was conducted to investigate the association of four variants of the CRP gene (1444C/T, -717T/C, 1861C/T, and 1919A/T) and two variants of the IL-6 gene (-174G/C and 597G/A) with OSA in a cohort of European American and Greek children. METHODS: The genetic risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (ORG), which is a model-free approach. The mode of inheritance was assessed using the degree of dominance index. The impact of haplotypes was also examined. RESULTS: In the American population, the allele contrast and the model-free approach produced significant ORs for the CRP 1444C/T variant (OR, 3.82 [95% confidence interval {CI}, 1.91-7.63] and ORG, 4.37 [95% CI, 1.96-9.76]), respectively, and the mode of inheritance was recessiveness of allele T. Significance was also shown for the CRP 1919A/T variant (OR, 2.45 [95% CI, 1.23-4.85] and ORG, 2.76 [95% CI, 1.26-6.03]) with the mode of inheritance being nondominance of allele T. For the IL-6-174G/C variant, there was an indication of recessiveness of allele C. Finally, the IL-6-174C/IL-6 597A haplotype was associated with OSA. In the Greek population, no association was detected for any variant or haplotype. CONCLUSIONS: Genetic variation in the IL-6/CRP pathway was associated with increased risk for OSA in European American children and may account for the higher CRP levels in the context of pediatric OSA compared to Greek children.

Substance P and neurokinin 1 receptors as potential therapeutic targets in children with OSA.

BACKGROUND: Increased substance P (SP) levels and abundant expression of neurokinin (NK) 1 receptor in adenotonsillar tissues of children with OSA but not recurrent tonsillar infection (RI) suggest that NK1 antagonists could be useful in treating OSA. METHODS: The effects of SP and the NK1 antagonist GR-82334 were examined on mixed cell cultures prepared from dissociated tonsils harvested intraoperatively from children with OSA and RI. Proliferation was assessed by [3H]-thymidine or 5-ethynyl-2'-deoxyuridine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-α, IL-6, IL-1ß) was assessed in supernatants by enzyme-linked immunosorbent assay. RESULTS: SP elicited dose-dependent increases in tonsillar cell proliferation in mixed cell cultures from children with OSA but not with RI (P < .0001). The NK1 antagonist exhibited dose-dependent reductions in cellular proliferative rates in OSA-derived cell cultures but not in RI-derived mixed cell cultures (P < .00001). SP treatment was associated with increased TNF-α and IL-6 production, and GR-82334 abrogated SP effects, as well as reduced basal cytokine release (P < .0001). CONCLUSIONS: SP pathways appear to underlie intrinsic proliferative and inflammatory signaling pathways in tonsillar tissues from children with OSA but not with RI. Selective disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of pediatric OSA.

Circulating adropin concentrations in pediatric obstructive sleep apnea: potential relevance to endothelial function.

OBJECTIVE: To test the hypothesis that concentrations of adropin, a recently discovered peptide that displays important metabolic and cardiovascular functions, are lower in obstructive sleep apnea (OSA), especially when associated with endothelial dysfunction. STUDY DESIGN: Age-, sex-, and ethnicity-matched children (mean age, 7.2 ± 1.4 years) were included into 1 of 3 groups based on the presence of OSA in an overnight sleep study, and on the time to postocclusive maximal reperfusion (Tmax >45 seconds) with a modified hyperemic test. Plasma adropin concentrations were assayed using a commercial enzyme-linked immunosorbent assay kit. RESULTS: Among controls, the mean morning adropin concentration was 7.4 ng/mL (95% CI, 5.2-16.3 ng/mL). Children with OSA and abnormal endothelial function (EF) (OSA(+)/EF(+) group) had significantly lower adropin concentrations (2.7 ± 1.1 ng/mL; n = 35) compared with matched controls (7.6 ± 1.4 ng/mL; n = 35; P < .001) and children with OSA and normal EF (OSA(+)/EF(-) group; 5.8 ± 1.5 ng/mL; n = 47; P < .001). A plasma adropin concentration <4.2 ng/mL reliably predicted EF status, but individual adropin concentrations were not significantly correlated with age, body mass index z-score, obstructive apnea-hypopnea index, or nadir oxygen saturation. Mean adropin concentration measured after adenotonsillectomy in a subset of children with OSA (n = 22) showed an increase in the OSA(+)/EF(+) group (from 2.5 ± 1.4 to 6.4 ± 1.9 ng/mL; n = 14; P < .01), but essentially no change in the OSA(+)EF(-) group (from 5.7 ± 1.3 to 6.4 ± 1.1 ng/mL; n = 8; P > .05). CONCLUSION: Plasma adropin concentrations are reduced in pediatric OSA when endothelial dysfunction is present, and return to within normal values after adenotonsillectomy. Assessment of circulating adropin concentrations may provide a reliable indicator of vascular injury in the context of OSA in children.