Montelukast for Children with Obstructive Sleep Apnea: Results of a Double-Blind, Randomized, Placebo-Controlled Trial.

RATIONALE: Obstructive sleep apnea (OSA) is highly prevalent in children and is usually treated by adenotonsillectomy. Nonsurgical therapies for OSA consist primarily of antiinflammatory approaches and have gained popularity, but their efficacy remains to be critically examined. OBJECTIVES: To determine the effect of montelukast on pediatric OSA. METHODS: A prospective randomized double-blind controlled trial of polysomnographically diagnosed OSA in children ages 2-10 years who were treated with either oral montelukast (4 or 5 mg daily) or placebo for 16 weeks. Adherence to the medication was ascertained using automated timed pill dispensers along with weekly telephonic reminders. MEASUREMENTS AND MAIN RESULTS: Ninety-two children diagnosed with OSA were approached, and 64 (69.6%) agreed to participate. Of these, 57 (89.0%) completed the 16-week trial, 28 in the montelukast group and 29 in the placebo group. Age, sex, and percentage of obesity were similar in the two groups, as were initial apnea-hypopnea index (AHI) scores. Overall, intention-to-treat analyses revealed that beneficial effects occurred in 20 children receiving montelukast (71.4%), whereas only 2 (6.9%) of the children receiving placebo showed reductions in AHI score (P < 0.001). Indeed, AHI decreased from 9.2 ± 4.1/hour total sleep time (TST) to 4.2 ± 2.8/hour TST (P < 0.0001) in montelukast-treated children, whereas in children receiving placebo, the AHI did not change (from 8.2 ± 5.0/h TST before to 8.7 ± 4.9/h TST at completion of the trial). CONCLUSIONS: When compared with placebo, montelukast for 16 weeks effectively reduced the severity of obstructive sleep apnea in children 2-10 years of age. These results support a therapeutic role for leukotriene modifiers in pediatric OSA provided that long-term trials confirm current findings. Clinical trial registered with www.clinicaltrials.gov (NCT 00599534).

Predictive Soft Tissue Airway Volume Analysis in Mandibular Distraction: Pushing The Envelope in Surgical Planning for Obstructive Sleep Apnea.

Three-dimensional computed tomography has been used in both preoperative planning of mandibular distraction osteogenesis and in the evaluation of postoperative resolution of tongue-based airway obstruction. The authors present a case report using software to predict postdistraction airway volume during virtual surgical planning (VSP) of mandibular distraction osteogenesis in a 7 year old. The predicted increase in airway volume derived from VSP was 33.57% (1716 mm(3) preoperatively to 2292 mm(3) postvirtual distraction). Based on the three-dimensional computed tomography, the actual airway volume increased to 2211 mm(3) postoperatively, a 28.85% increase.The implications of this advancing technology are far-reaching. An illustrative case is presented herein to demonstrate the efficacy of the airway prediction and its limitations. The authors believe that, with continued investigation, this novel approach may be a standard feature of all VSP sessions for the treatment of tongue-based airway obstruction.

Pupillometric findings in children with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) leads to intermittent hypoxia, activation of the sympathetic nervous system, and eventually cardiovascular morbidity. Alterations in autonomic nervous system (ANS) tone and reflexes are likely to play major roles in OSA-associated morbidities, and have been identified in a subset of children with OSA. OBJECTIVES: To evaluate whether pupillometry, a noninvasive and rapid bedside test for the assessment of autonomic nervous system dysfunction (ANS), would detect abnormal ANS function in children with OSA. METHODS: Children ages 2-12 years underwent polysomnography (PSG), and were divided based on PSG findings into two groups; Habitual Snorers (HS; AHI < 1 h/TST, n = 17) and OSA (AHI > 1 h/TST, n = 49), the latter then sub-divided into AHI severity categories (>1 but <5, >5 but <10, and >10 h/TST). Pupillometric measurements were performed during the clinic visit in a dark room using an automated pupillometer device. RESULTS: A total of 66 subjects with a mean age of 7.3 ± 2.6 years were recruited. There were no statistically significant differences between any of the groups, even when comparing severe OSA (n = 15) and HS in any of the measures related to pupillary reflexes. However, mild, yet significant increases in systolic blood pressure and morning plasma norepinephrine levels were detected in the severe OSA group. CONCLUSION: Although ANS perturbations are clearly present in a proportion of children with OSA, particularly those with severe disease, pupillary responses do not appear to provide a sensitive method for the detection of ANS dysfunction in OSA children.

Nitric oxide production by monocytes in children with OSA and endothelial dysfunction.

OSA (obstructive sleep apnoea) is associated with a higher risk for alterations in post-occlusive hyperaemia, an eNOS (endothelial NO synthase)-dependent endothelial response. However, since not all children manifest endothelial dysfunction, we hypothesized that differences in circulating monocyte subsets and NO production may underlie the vascular phenotype in paediatric OSA. Matched pre-pubertal children with OSA with abnormal endothelial function (OSAab) and with normal endothelial function (OSAn), and controls (CO) were recruited. Peripheral blood mononuclear cells were subtyped into CD14+ and CD16+ cells, and NO production was assessed using flow cytometry. Endothelial dysfunction was defined as Tmax (time to reach maximal reperfusion)>45 s by laser Doppler flowmetry. A total of 11 OSAab, 12 OSAn and 12 CO-matched children completed the study. The OSAab group had increased CD16+ and decreased CD14+ cell numbers. They also had increased CX3CR1 (CX3C chemokine receptor 1) expression in CD16+ monocytes (P<0.01). Furthermore, monocytes from the OSAab group exhibited overall reduced NO production (787±71 compared with 1226±229 and 1089±116 median fluorescence intensity in the OSAn group and CO children respectively; P<0.01). Significant bivariate associations emerged between NO production, monocyte subsets, CX3CR1 in CD16+ monocytes, the CD14+/CD16+ ratio and Tmax. Thus OSA in children is associated with increased numbers of pro-inflammatory monocytes and reduced NO production in circulating monocytes that are closely associated with endothelial function.

Overnight polysomnography versus respiratory polygraphy in the diagnosis of pediatric obstructive sleep apnea.

BACKGROUND: Substantial discrepancies exist in the type of sleep studies performed to diagnose pediatric obstructive sleep apnea (OSA) in different countries. Respiratory polygraphic (RP) recordings are primarily performed in sleep laboratories in Europe, whereas polysomnography (PSG) constitutes the majority in the US and Australia. Home RP show consistent apnea-hypopnea index (AHI) underscoring, primarily because the total recording time is used as the denominator when calculating the AHI compared to total sleep time (TST). However, laboratory-based RP are less likely affected, since the presence of sleep technicians and video monitoring may enable more accurate TST estimates. We therefore examined differences in AHI in PSG and in-lab RP, and whether RP-based AHI may impact clinical decision making. METHODS: Of all the children assessed for possible OSA who underwent PSG evaluation, 100 were identified and divided into 4 groups: (A) those with AHI < 1/h TST (n = 20), (B) 1 ≤ AHI < 5/h TST (n = 40), (C) 5 ≤ AHI < 10/h TST (n = 20), and (D) AHI ≥ 10/h TST (n = 20). Electroencephalography, electrooculography, and electromyography channels were deleted from the original unscored recordings to transform them into RP, and then rescored in random sequence. AHI-RP were compared to AHI-PSG, and therapeutic decisions based on AHI-RP and AHI-PSG were formulated and analyzed using clinical details derived from the patient's clinic letter. RESULTS: Bland Altman analysis showed that in lab RP underestimated the AHI despite more accurate estimates of TST. This underestimation was due to missed hypopneas causing arousals without desaturation. Basing the therapeutic management decision on RP instead of PSG results changed the clinical management in 23% of all patients. The clinical management for patients in groups A and D was unaffected. However, 27.5% of patients in group B would have been given no treatment, as they would be diagnosed as having no OSA (AHI < 1/h TST) when they should have received a trial of anti-inflammatory therapy or been referred for ear, nose, and throat (ENT) review. Sixty percent of patients in group C would have received either a trial of medical treatment to treat mild OSA or no treatment, instead of referral to ENT services or commencement of continuous positive airway pressure. CONCLUSION: Apnea-hypopnea index (AHI) is underestimated in respiratory polygraphy (RP), and the disparity in AHI-RP and AHI-polysomnography can significantly affect clinical management decisions, particularly in children with mild and moderate obstructive sleep apnea (1 < AHI < 10/h total sleep time).

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.

T regulatory lymphocytes and endothelial function in pediatric obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a low-grade inflammatory disease affecting the cardiovascular and metabolic systems. Increasing OSA severity reduces T-regulatory lymphocytes (Tregs) in OSA children. Since Tregs modulate endothelial activation, and attenuate insulin resistance, we hypothesized that Tregs are associated with endothelial and metabolic dysfunction in pediatric OSA. METHODS: 50 consecutively recruited children (ages 4.8-12 years) underwent overnight polysomnography and fasting homeostatic model (HOMA) of insulin resistance was assessed. Percentage of Tregs using flow cytometry, and endothelial function, expressed as the time to peak occlusive hyperemia (Tmax), were examined. In a subgroup of children (n = 21), in vitro Treg suppression tests were performed. RESULTS: Circulating Tregs were not significantly associated with either BMI z score or HOMA. However, a significant inverse correlation between percentage of Tregs and Tmax emerged (p<0.0001, r = -0.56). A significant negative correlation between Tregs suppression and the sleep pressure score (SPS), a surrogate measure of sleep fragmentation emerged (p = 0.02, r = -0.51) emerged, but was not present with AHI. CONCLUSIONS: Endothelial function, but not insulin resistance, in OSA children is strongly associated with circulating Tregs and their suppressive function, and appears to correlate with sleep fragmentation. Thus, alterations in T cell lymphocytes may contribute to cardiovascular morbidity in 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.

Alterations in circulating T-cell lymphocyte populations in children with obstructive sleep apnea.

STUDY OBJECTIVES: Changes in lymphocyte phenotype and functionality have been described in adult patients with obstructive sleep apnea (OSA). We hypothesized that OSA is associated with T lymphocyte alterations in children, particularly in T regulatory lymphocytes (T regs), and aimed to characterize circulating T lymphocyte subsets in children with OSA. DESIGN: Cross-sectional. SETTING: Kosair Children's Hospital (Louisville, KY, USA) and Comer Children's Hospital (Chicago, IL, USA). PARTICIPANTS: Consecutively recruited children being evaluated for habitual snoring. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Overnight polysomnography (PSG) was performed and a fasting blood sample was obtained from the patients. Flow cytometry was performed on peripheral blood mononuclear cells stained for CD3, CD4, CD8, CD25, FOXP3, interleukin-4 (IL-4), interferon-γ (IFN-γ), and IL-17. Patients were divided into three groups based on their PSG: controls (apnea-hypopnea indices [AHI] < 1/h total sleep time [TST]), mild OSA (1 ≤ AHI < 5/hTST), moderate-severe OSA (AHI ≥ 5/h TST). The percentage of CD4+ and T reg lymphocytes differed across groups. Children with moderate-severe OSA had significantly reduced T reg than control children (median [interquartile range] 4.8 [3.8-5.7% CD4+] versus 7.8 [7.0-9.2% CD4+]; P < 0.001). There were also significant differences in the percentage of T helper 1 (Th1) lymphocytes and in Th1:Th2 ratios between groups. Children with moderate-severe OSA had increased Th1 cells (P = 0.001) and Th1:Th2 ratios (P = 0.0026) compared with children with mild OSA and control children. Associations between AHI and T reg (P = 0.0003; r = -0.46), CD4+ lymphocytes (P = 0.0047; r = -0.37), and Th1:Th2 ratios (P = 0.0009; r = 0.43) emerged. In addition, the percentage of T reg was inversely correlated with Th1:Th2 ratios (P = 0.029; r = -0.29). CONCLUSIONS: Pediatric OSA is associated with reduced T reg population and altered Th1:Th2 balance toward Th1 predominance, suggesting a shift to a proinflammatory state. The changes in lymphocytic phenotypes associated with OSA may contribute to the variance in systemic inflammation and downstream morbidities associated with this condition.