pii: sp- 00072-16

http://dx.doi.org/10.5665/sleep.6084

PEDIATRICS

Upper Airway Vibration Perception in School-Aged Children with Obstructive Sleep Apnea Ignacio E. Tapia, MD, MS1,2; Ji Young Kim, PhD3; Mary Anne Cornaglia1; Joel Traylor, BS1; George J. Samuel1; Joseph M. McDonough, MA1; Carole L. Marcus, MBBCh1,2 1 Sleep Center, The Children’s Hospital of Philadelphia, Philadelphia, PA; 2Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3Biostatistics Core, Clinical and Translational Research Center, The Children’s Hospital of Philadelphia. Philadelphia, PA

Study Objectives: Children with the obstructive sleep apnea (OSA) have impaired upper airway two-point discrimination compared to controls. In addition, blunted vibration threshold detection (VT) in the palate has been recognized in adults with OSA, but has not been studied in children. Both findings are indicative of a defect in the afferent limb of the upper airway dilator reflex that could prevent upper airway dilation secondary to airway loading, resulting in airway collapse. We hypothesized that children with OSA have impaired palate VT compared to controls, and that this improves after OSA treatment. Methods: Case-control study. Children with OSA and healthy non-snoring controls underwent polysomnography and palate VT measurements. Children with OSA were retested after adenotonsillectomy. Results: 29 children with OSA (median [interquartile range] age = 9.5 [7.5–12.6] years, obstructive apnea-hypopnea index [OAHI] = 11.3 [5.7–19.5] events/h, BMI z = 1.8 [1.3–2.1]) and 32 controls (age = 11.2 [9.3–13.5] years, P = 0.1; OAHI = 0.5 [0.1–0.7] events/h, P < 0.001; BMI z = 1 [0.3–1.7], P = 0.004) were tested. OSA palate VT (1.0 [0.8–1.5] vibration units) was similar to that of controls (1 [0.8–1.3], P = 0.37). 20 children with OSA were retested 4.4 (3.2–7.1) months after treatment. OAHI decreased from 13.1 (5.8–19) to 0.6 (0.2–2.5) events per hour (P < 0.001) postoperatively, but palate VT did not change (before = 1 [0.7–1.5], after = 1.2 [0.8–1.4], P = 0.37). Conclusions: Children with OSA and controls have similar palate VT. Unlike in adults, palate VT does not seem to be affected by childhood OSA. Keywords: obstructive sleep apnea, children, upper airway, vibration Citation: Tapia IE, Kim JY, Cornaglia MA, Traylor J, Samuel GJ, McDonough JM, Marcus CL. Upper airway vibration perception in school-aged children with obstructive sleep apnea. SLEEP 2016;39(9):1647–1652. Significance Vibration perception is unaffected in children with OSA despite impaired two-point discrimination in the tongue and palate, and impaired respiratoryrelated evoked potentials during wakefulness and sleep; therefore, abnormal upper airway vibration perception does not appear to be a primary contributor for pediatric OSA.

INTRODUCTION Both the afferent and efferent limbs of upper airway (UA) reflexes need to be functional in order to maintain UA patency. Abnormalities affecting the afferent limb of the UA dilator reflex can impair the ability to perceive and/or process UA loading. This can lead to failure of UA dilatation, resulting in UA collapse. In children, the afferent limb of the UA dilator reflex has been studied using psychophysical methods, such as twopoint discrimination. It has been shown that children with the obstructive sleep apnea (OSA) have impaired two-point discrimination in the tongue and palate compared to normal non-snoring healthy controls.1 Objective measurements, such as respiratory related evoked potentials (RREP) have also been performed in children with OSA. Briefly, RREP are averaged surface electroencephalographic responses to multiple respiratory mechanical stimuli applied during inspiration and, therefore, are objective measures of respiratory afferent sensory processing. Specifically, children with OSA have been shown to have blunted RREP during sleep and delayed RREP during wakefulness compared to normal non snoring controls.2,3 Importantly, blunted RREP during sleep did not improve after treatment of OSA, and delayed RREP during wakefulness only partially improved after treatment.2,3 These findings suggest that UA afferent limb deficits are partially reversible at least during wakefulness, and highlight the importance of testing participants before and after treatment of OSA. SLEEP, Vol. 39, No. 9, 2016

Vibration threshold (VT) measurement in the soft palate is another aspect of upper airway sensory function that can be tested. Palate VT has been shown to be blunted in adults with OSA compared to controls, and to mildly improve after treatment with continuous positive airway pressure.4 In addition, research in adult subjects with OSA suggested that impaired palate VT was secondary to local neurological damage due to snoring.5 However, it is unknown whether this VT impairment occurs early on during the course of OSA or is a late complication of OSA secondary to, for example, prolonged gas exchange abnormalities during sleep or long duration of snoring. This palate VT blunting could also be a pre-existing condition that contributes to OSA and worsens over time, causing a vicious cycle. Hence, it is relevant to determine whether VT improves after OSA treatment in children. In fact, children are an ideal population to study sensory function because they have a shorter clinical course of OSA than adults. For example, symptoms in adults, such as snoring, can be present for decades before the official diagnosis of OSA. In addition, children have been exposed to less comorbidities, substances or medications that could affect UA sensation, such as smoking and sedatives. This information could help establishing whether palate VT blunting is primary or secondary. Therefore, we measured palate VT in controls compared with children with OSA before and after treatment. We hypothesized that children with OSA have impaired palate VT that does not resolve after treatment of OSA.

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and bilateral tibialis anterior EMG. Subjects were continuously observed by a polysomnography technician, and were recorded on video with the use of an infrared video camera. Studies were scored using standard pediatric rules.8

Figure 1—Vibratron II: Controller and vibration post.

METHODS Study Group Children between 6–16 years of age were included. The younger age limit was selected to exclude children who could not understand and cooperate with testing. The older age limit was chosen to avoid overlap with adult OSA. Patients with OSA were recruited from the Sleep Center at The Children’s Hospital of Philadelphia following a recent clinical polysomnogram. Normal, non-snoring controls were recruited from the general community by means of advertisements. For screening purposes, controls completed the validated Pediatric Sleep Questionnaire to exclude those with suspected sleep-disordered breathing.6 Those who passed the screening underwent a polysomnogram to ensure normalcy. Other exclusion criteria for OSA and controls included significant medical conditions other than OSA, medications that could interfere with sensory perception (such as benzodiazepines and opiates), and a history of UA surgery. The control and OSA groups were matched for age and gender. Children with OSA underwent a repeat polysomnogram and sensory testing after a clinically indicated adenotonsillectomy to assess improvement. The Institutional Review Board of the Children’s Hospital of Philadelphia approved the study. Informed consent was obtained from the parents/guardians of subjects, and assent from the children. Polysomnography was performed as previously described.7 Briefly, a Rembrandt polysomnography system (Embla, Broomfield, CO) recorded the following parameters: electroencephalogram (C3/A2, C4/A1, F3A2, F4A1, O1/A2, O2/A1), left and right electroculograms, submental electromyogram (EMG), chest and abdominal wall motion using respiratory inductance plethysmography, heart rate by electrocardiogram, arterial oxygen saturation (SpO2) by pulse oximetry (Masimo, Irvine, CA); end-tidal PCO2 (PETCO2), measured at the nose by infrared capnometry (Novametrix Medical System, Inc., Wallingford, CT), airflow using a 3-pronged thermistor (ProTech Services, Inc., Mukilteo, WA), nasal pressure by a pressure transducer (Pro-Tech Services, Inc., Walnut Cove, NC), SLEEP, Vol. 39, No. 9, 2016

Sensory Function Testing OSA and controls underwent vibration threshold testing during wakefulness while the child was seated comfortably. Testing was performed by an investigator blinded to the subject’s OSA status. Vibration threshold testing was performed with a device (Vibratron-II, Physitemp, NJ) capable of delivering a vibratory stimulus over a range of amplitudes. The device consists of a controller and a vibrating post (Figure 1). First, VT was established by testing sensation on the subject’s hand to ensure peripheral sensory normalcy and acclimate participants to testing. This was followed by VT determination at the oropharyngeal mucosa on the soft palate because this location is the most exposed to snoring-induced vibration.9 For testing of the oropharyngeal mucosa, the transducer was fixed to a stand of adjustable height placed in front of the participant. The position of the stand was adjusted so that the probe was against the oropharyngeal mucosa with sufficient pressure to slightly (1 mm) indent the mucosa, and the probe was maintained in this position throughout testing. The tester wore a headlamp to ensure that the vibrating probe was always in proper position, applied with the appropriate pressure, and not in contact with any other oral structures. VT was determined using the method of limits.10 Briefly, in the method of limits, stimuli are presented in ascending or descending order, with the participant making a response after each presentation. A stimulus series is continued until the response changes. At that point, a new series begins in the opposite order. The point at which the participant’s response changes provides information about the perceptual threshold. Participants were instructed to say “I feel it” and “I don’t feel it” when testing vibration on the hand, and to raise a hand when they felt vibration in the palate. Three ascending and three descending trials were performed on the hand. Six ascending trials were performed in the oropharynx; descending trials were not performed to avoid eliciting the gag reflex. The mean of the six vibration unit values for the points of detection and extinction were obtained to yield the vibratory detection threshold for the hand. The mean of the six vibration unit values for the points of detection was obtained to yield the vibratory detection threshold for the palate.

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Data Analysis Statistical analysis was performed with SigmaStat 12.5 (Systat Software Inc., San Jose, CA) and R version 3.1.0 (R Foundation for Statistical Computing, www.R-project.org).11 The Kolmogorov-Smirnov test was used to test for normality for continuous variables. Continuous data are presented as median (IQR) to accommodate the skewness in some of the variables. and categorical data are presented as n (%). OSA and control groups were compared using the Wilcoxon rank-sum test for continuous variables, and the Fisher exact test for categorical variables. Paired and unpaired statistics were used as appropriate. A P value < 0.05 was required for significance. Upper Airway Vibration in Pediatric OSAS—Tapia et al.

Table 1—Study group demographics and polysomnography results. OSA (n = 29) 9.5 (7.2, 12.6) 19 (65.5%) 1.8 (1.3, 2.1) 17 (58.6%) 11.3 (5.7, 19.5) 88.0 (84.0, 91.0) 0.2 (0.0, 1.0) 55.5 (54.4, 58.6) 13.0 (3.3, 29.0)

Age, year Male, n (%) Body mass index z score Obese, n (%) Apnea-hypopnea index, events/h SpO2 nadir, % Time with SpO2 < 90%, % TST Peak end-tidal CO2, mm Hg Time with end-tidal CO2 ≥ 50 mm Hg, % TST

Controls (n = 32) 11.2 (9.3, 13.5) 14 (43.8%) 1.0 (0.3, 1.7) 10 (31.3%) 0.5 (0.1, 0.7) 93.0 (92.0, 95.0) 0.0 (0.0, 0.0) 52.2 (50.8, 54.5) 0.1 (0.0, 1.2)

P value 0.10 0.12 0.004 0.041 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

OSA, obstructive sleep apnea; SpO2 (arterial oxyhemoglobin saturation; TST, total sleep time. Data shown as median (interquartile range) or n (%).

Table 2—Vibration thresholds in children with OSA compared to controls. OSA 0.8 (0.7, 1.1) 0.7 (0.6, 0.9) 1.0 (0.8, 1.5)

Ascending vibration threshold right index finger (vibration units) Descending vibration threshold right index finger (vibration units) Vibration threshold in palate (vibration units)

Controls 0.8 (0.7, 0.9) 0.7 (0.6, 0.8) 1.0 (0.8, 1.3)

P value 0.30 0.60 0.37

OSA, obstructive sleep apnea.

Table 3—Vibration thresholds (vibration units) in the palate and fingers in children with OSA compared to controls grouped by obesity status. OSA

Controls

P value

Palate Obese Non-obese

n = 17 n = 12

1.3 (0.8–1.6) 1.0 (0.7–1.3)

n = 10 n = 22

0.7 (0.6–0.9) 1.2 (0.9–1.4)

0.007 0.12

Right index finger (ascending) Obese Non-obese

n = 17 n = 12

0.9 (0.7–1.4) 0.7 (0.7–0.8)

n = 10 n = 22

0.8 (0.6–0.8) 0.8 (0.7–1.0)

0.12 0.46

Right index finger (descending) Obese Non-obese

n = 17 n = 12

0.9 (0.6–0.9) 0.7 (0.6–0.7)

n = 10 n = 22

0.6 (0.6–0.8) 0.7 (0.6–0.8)

0.42 0.59

OSA, obstructive sleep apnea.

A probabilistic index was calculated, which is defined by P(OSA > Control) = U / (nOSA × nControl), where U is the Mann-Whitney U statistic, and nOSA and nControl are the group sample sizes.11 It is an intuitive measure of the effect size, representing the probability that the palate VT of an OSA participant is higher than that of a randomly chosen control subject. A 50% probability index means that the palate VT of an OSA participant is the same as that of a control, similar to a toss of a coin. RESULTS Study Group Characteristics The subjects’ characteristics are shown in Table 1. Participants with OSA and controls had similar age and gender distributions. The OSA group had moderate OSA by pediatric standards.12 Participants with OSA were more obese than controls. SLEEP, Vol. 39, No. 9, 2016

Vibration Threshold Results are presented in Table 2. Vibration thresholds in the right index finger and palate were similar in children with OSA and controls. Similarly, there was no difference in palatal VT between the two groups. The Probabilistic index for the palate VT was 0.57, indicating that the observed probability that an OSA participant had a higher palate VT than a control was 57%. This is not greater than chance. Due to the difference in obesity between groups, OSA and controls results were also analyzed by obesity status. As presented in Table 3, obese participants with OSA had blunted palate VT compared to obese controls (P = 0.007).

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Vibration Threshold after OSA Treatment Children with OSA underwent adenotonsillectomy as per standard clinical practice.13 Twenty children (69%) with OSA were retested after treatment. Of the remaining children, 3 declined Upper Airway Vibration in Pediatric OSAS—Tapia et al.

Table 4—Vibration thresholds in the palate in children with OSA after treatment grouped by obesity status and resolution of OSA after treatment. Palate VT after treatment ± SD (vibration units)

Resolved OSA (n = 13)

Residual OSA (n = 7)

P value

Obese OSA (n = 11)

Non-obese OSA (n = 9)

P value

1.1 ± 0.4

1.2 ± 0.3

0.78

1.1 ± 0.4

1.3 ± 0.4

0.25

OSA, obstructive sleep apnea.

Figure 3—Vibration threshold in the palate in children with OSA before and after treatment. The box represents the interquartile range; the central line represents the median; the whiskers represent the 5th and 95th percentiles; and the dots represent the outliers. Vibration threshold in the palate did not change significantly in children with obstructive sleep apnea before and after treatment.

Figure 2—Change in obstructive apnea-hypopnea index following surgery. The obstructive apnea-hypopnea index decreased significantly in children with obstructive sleep apnea following adenotonsillectomy. OAHI, obstructive apnea-hypopnea index.

further research, 3 families chose CPAP over surgery, one chose weight loss and 2 were lost to follow up. Polysomnography and VT testing were repeated 4.4 [3.2–7.1] months after treatment. The AHI decreased from 13.1 [5.8–19] to 0.6 [0.2–2.5] events per hour (P < 0.001) (Figure 2). Seven children (35%) had residual mild obstructive sleep apnea after treatment (AHI range: 1.6 to 5.1 events/h). VT in the palate did not change after OSA treatment (Figure 3). No differences were observed in obese vs. non-obese participants or in participants with resolved OSA vs. those with residual OSA (Table 4). Palate VT in the 11 obese OSA participants who were tested before and after surgery showed a trend towards a decrease from 1.3 ± 0.5 to 1.1 ± 0.4, P = 0.09. The probabilistic index for the palate VT in obese vs. non-obese participants before and after surgery was 0.85 with a power of 83.6%. This indicates that the sample size was powered to detect the difference between obese and non-obese OSA participants before and after treatment. DISCUSSION This study has provided palate VT data in normal non-snoring children and has shown that, overall, palate VT appears to be intact in children with OSA. However, obese children with OSA have lower palate VT compared to obese controls at baseline. In addition, palate VT did not change after treatment of OSA. These results suggest that, in general, vibration perception is unaffected in children with OSA despite impaired two-point discrimination in the tongue and palate, and impaired RREP during wakefulness and sleep. Thus, abnormal upper airway vibration perception is unlikely to be a primary contributor to the SLEEP, Vol. 39, No. 9, 2016

pathogenesis of OSA in children considering that the palate VT differences do not seem large enough to have a clinical effect, especially in comparison to the differences in adult data. UA Sensory Function Studies The patency of the upper airway relies on both the afferent and efferent limbs of upper airway reflexes. Previous research has shown that children with OSA have blunted upper airway dynamic responses to respiratory stimuli such as hypercapnia and airway subatmospheric pressure.14–17 These decreased responses could be attributed to compromised function of the efferent UA reflex limb.14–16 However, the afferent limb of the upper airway reflexes, such as those originating from UA mucosal sensory receptors, may play a role in the termination of apneas by mediating UA tone.18–21 For example, studies in adults have demonstrated that attenuation of UA mucosal sensation by topical anesthesia increases the tendency to airway collapse.20,22 In addition, UA anesthesia also induces apneas and hypopneas during sleep in normal subjects19 and increases the frequency of obstructive events in snorers.18,21 These findings suggest that impairment of UA mucosal sensory function could contribute to UA collapse during sleep. The afferent limb of the UA reflexes has been studied by psychophysical methods1,4,23–25 and RREP.2,3 Psychophysical methods, such as two-point discrimination, VT, and inspiratory load perception allow investigators to relate the physiological functions of the receptors and afferents to the subjective

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experience of the subject. Children with OSA have been shown to have blunted two-point discrimination in the tongue and palate compared to normal non-snoring healthy controls.1 Inspiratory load perception studies performed in children 26 and adults have also demonstrated impaired mucosal sensory function in subjects with OSA.4,23,27,28 Interestingly, the lower VT response observed in adults29,30 has been attributed to a local neuropathy caused by many years of snoring, based on signs of neurogenic damage in palatopharyngeal muscle biopsies; the signs of neurogenic damage were more severe in those subjects with more severe OSA.31 Similar studies have not been performed in children. To date, the only publication analyzing palatopharyngeal muscle biopsies in children with OSA compared to normal controls and snorers did not find histopathological differences between the three groups.32 Palate VT in Children vs. Adults Until now, it was unknown whether palate VT in children was different than that reported in adults. Kimoff et al. reported a mean VT of 2.2 ± 0.1 (SD) vibration units for adult controls,4 which is double the values of the control children reported here. Interestingly, palate VT in adults with OSA was 4 times the values of this study’s OSA participants. This suggests that, in general, otherwise normal children are able to perceive vibration better than adults. In fact, pediatric OSA is different from the adult condition. Children with OSA tend to have preserved sleep architecture,33 a higher arousal threshold,34 and a predominance of partial rather than complete UA obstruction.35,36 Thus, there are pathophysiologic differences in the condition at different ages. The striking differences in VT across the age spectrum could also be due to psychophysical confounders, such as children being tired or not understanding instructions. However, this is unlikely because testing was performed in a standardized fashion, using methods shown to be as accurate as more invasive techniques.37 Duration of OSA in Children The prevalence of OSA in children has been estimated between 1% and 5%,12 and that of snoring, the cardinal symptom of OSA in pediatrics,38 in up to 12%. There is a wide range of reported snoring, from 1.5% to 27.6%,12 due to the type of questionnaires used and possibly parental recall. Caregivers typically have difficulty pinpointing the start date of snoring, making it difficult to determine the duration of OSA. Considering there are no longitudinal studies following a cohort of full-term newborns until adult age to determine risk factors for OSA, the clinical course of OSA in children is unknown. However, it could be assumed that is rather short as many young children are diagnosed with OSA.12 Specifically, the participants of this manuscript were all school-aged. Therefore, palate VT results presented here relate to a short clinical course. Upper respiratory infections have been associated with neurogenic inflammation, which has also been reported in UA lymphoid tissues in children with OSA.39 However, no clear link has been established between recurrent upper respiratory infections and decreased VT perception. Participants of this study did not have upper respiratory infections at the time of testing. This study has also shown that obese children with OSA had lower VT perception compared to obese controls at baseline. SLEEP, Vol. 39, No. 9, 2016

Considering that UA fat deposition has been described in obese subjects40,41 and may be expected to blunt sensation, we would expect to find lower VT perception in all obese participants. Therefore, the difference observed between obese OSA and obese controls could be due to snoring. It is possible that vibrational damage may affect obese children only. This highlights the need for longitudinal studies in children, ideally with palatine biopsy correlations to further characterize OSArelated UA changes. Limitations VT was tested, by an investigator blinded to the participants OSA status, using the method of limits, which is a well-established psychophysical method. Psychophysical methods require the active participation of the subject. Therefore, results can be affected by psychological confounding factors. However, when carried out accurately and in a standardized manner, as in this protocol, these methods can be as valid as the more invasive neurophysiological techniques.37 However, to the best of our knowledge, VT in the upper airway measured by psychophysical methods has not been compared with invasive neurophysiological techniques. The sample size was of a moderate size. However, the study was adequately powered based on available palate VT data.4 Based on this, the 1:1 group allocation rate, and the possibility that this manuscript’s data distribution might not be Gaussian, the Mann-Whitney rank sum test was used as a non-parametric alternative for the power calculations. It indicated that a sample size of 29 in each group had 80% power to detect a probability of 0.71 or higher that palate VT in the control group was less than palate VT in the OSA group. The probabilistic index P(OSA > Control) for the palate VT observed from our sample was 0.57, which was lower than expected and confirmed the failure to reject the null hypothesis. Results could not be correlated with pathology or inflammation as palatine biopsy specimens and inflammatory markers were not part of this protocol. Finally, the exact duration of OSA was unknown. CONCLUSIONS In general, children with OSA have similar palate VT compared to controls at baseline, although obese children with OSA have blunted palate VT compared to obese controls. However, palate VT does not change after OSA treatment. These findings suggest that upper airway neuropathy is less prevalent in children than adults, and is unlikely to be a major contributor to or consequence of childhood OSA. Vibrational damage may affect obese children only, and further research is needed to better understand the pathophysiology of OSA in obese children.

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Upper Airway Vibration in Pediatric OSAS—Tapia et al.

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SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication February, 2016 Submitted in final revised form April, 2016 Accepted for publication May, 2016 Address correspondence to: Ignacio E. Tapia, MD, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, office 11403, Philadelphia, PA 19104; Tel: (215) 590-3749; Fax: (215) 590-3500; Email: [email protected]

DISCLOSURE STATEMENT This was not an industry supported study. Support was provided through AHA 10CRP376001, NIH UL1RR024134, and Research Electronic Data Capture (REDCap). The authors have indicated no financial conflicts of interest.

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Upper Airway Vibration in Pediatric OSAS—Tapia et al.

Upper Airway Vibration Perception in School-Aged Children with Obstructive Sleep Apnea.

Children with the obstructive sleep apnea (OSA) have impaired upper airway two-point discrimination compared to controls. In addition, blunted vibrati...
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