Ultrasound in Med. & Biol., Vol. 40, No. 11, pp. 2590–2598, 2014 Copyright Ó 2014 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.06.019
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Original Contribution SUBMENTAL ULTRASOUND MEASUREMENT OF DYNAMIC TONGUE BASE THICKNESS IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA JENG-WEN CHEN,*y CHUN-HSIANG CHANG,*y SHOU-JEN WANG,*y YEN-TEH CHANG,yz and CHIH-CHUNG HUANGx * Department of Otolaryngology Head and Neck Surgery, Cardinal Tien Hospital, New Taipei City, Taiwan; y School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; z Division of Pulmonary Medicine, Department of Internal Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan; and x Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan (Received 30 April 2014; revised 10 June 2014; in final form 30 June 2014)
Abstract—Dynamic tongue base thickness (TBT) may be an important anatomic factor in airway narrowing in patients with obstructive sleep apnea (OSA). The development of an accurate clinical assessment of the retroglossal airway in patients with OSA is still evolving. Submental ultrasound was used to investigate the association between measurements of TBT in response to negative airway pressure and the existence of OSA. Twenty OSA patients and 20 control participants underwent ultrasound measurement of TBT on eupneic breathing and with the Mueller maneuver, as well as clinical and polysomnographic assessments. Logistic regression analyses indicated that after adjustment for confounding factors, independent predictors of OSA included TBT in response to negative airway pressure, as measured by submental ultrasound with the Mueller maneuver (odds ratio: 2.11, 95% confidence interval: 1.15–3.87, p , 0.05), and the difference between TBT with the Muller maneuver and that without the Mueller maneuver (odds ratio: 2.47, 95% confidence interval: 1.09–5.58, p , 0.05). Ultrasound measurement of TBT during the Mueller maneuver provides a quantitative assessment of the retroglossal airway in OSA patients with minimal invasiveness and easy accessibility. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Obstructive sleep apnea, Ultrasound, Tongue base thickness, Mueller maneuver, Polysomnography.
physiologic effects of these respiratory events, even attended, laboratory-based PSG cannot precisely localize the sites of upper airway (UA) occlusion. Therefore, additional clinical tools for evaluating static and/or dynamic UA anatomy are needed not only for improved understanding of the biomechanics and pathophysiology of OSA, but also for improved patient management and treatment success. The oropharynx, with extension to the laryngopharynx, is the major anatomic location in which airway collapse occurs (Horner 1996; Rama et al. 2002). Obstructive sleep apnea is hypothesized to have resulted from specific evolutionary changes in the human UA that facilitate speech and language development. These changes cause posterior migration of the tongue base on the laryngeal aperture and considerable narrowing of the pharyngeal airway (Davidson 2003; Davidson et al. 2005). The human tongue is a highly mobile organ with interweaving but distinct skeletal muscle groups. A biomechanical analysis of the human tongue has been
INTRODUCTION Obstructive sleep apnea (OSA), a breathing disorder characterized by recurring episodes of partial or complete obstruction of the pharyngeal airway during sleep, can cause intermittent hypoxemia, frequent arousal and sleep fragmentation (Arens and Marcus 2004). Patients are often referred to health care professionals by concerned bed partners or parents who have witnessed apneas followed by snoring, choking or gasping (Myers et al. 2013). The diagnosis of OSA syndrome is based on clinical symptoms and episodes of apnea and hypopnea measured by polysomnography (PSG). Although PSG is the gold standard for diagnosing OSA and for recording
Address correspondence to: Chih-Chung Huang, Department of Biomedical Engineering, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan. E-mail: cchuang@mail. ncku.edu.tw Conflicts of Interest: This was not an industry-supported study. The authors have indicated no financial conflicts of interest. 2590
Tongue base thickness in obstructive sleep apnea d J.-W. CHEN et al.
performed with a geometric constitutive model (Kajee et al. 2013). Computational simulations based on this model have indicated that, even without active muscle contraction, these interwoven muscle fibers generate sufficient stiffness to partially overcome the gravitational forces when in the supine position. Only a select group of muscles must work simultaneously for efficient prevention of posterior displacement of the tongue base and, thus, airway collapse. This hypothesis was further tested in a recent study by Brown et al. (2013), who used a tagged cine magnetic resonance imaging technique to compare UA soft tissue mechanics during respiration in OSA patients and normal patients. They reported that patients with severe OSA usually exhibit minimal tongue movement during quiet breathing because of their difficulty dilating the restricted UA even in wakefulness. Several imaging modalities including X-ray cephalometry, computed tomography (CT) scanning and magnetic resonance imaging (MRI), have been used to analyze ‘‘static’’ predisposing factors in the UA anatomy of OSA patients while awake and while asleep. Numerous ‘‘dynamic’’ techniques such as ultrafast CT scanning, cine MRI, pressure measurements, fluoroscopy and acoustic reflections have also been used specifically to identify the severity of UA obstruction in OSA patients. Each method has unique advantages and limitations (Shepard et al. 1991; Faber and Grymer 2003; Stuck and Maurer 2008; Togeiro et al. 2010), which may explain the wide variation in the reported results. Together, these techniques for UA assessment have substantially improved the understanding of OSA. However, their use in daily practice is still limited. In contrast, other routinely used clinical tools such as cephalometry, fiberoptic nasopharyngoscopy with the Mueller maneuver (MM) and druginduced sleep endoscopy have provided little evidence of improved treatment outcomes (Stuck and Maurer 2008). The MM has been widely applied to simulate the pathophysiologic condition of OSA during wakefulness. Even though limited in subjectivity and nonquantitative, fiberoptic nasopharyngoscopy with the MM remains one of the most commonly used office procedures for evaluating UA in OSA patients. Other sophisticated imaging modalities are not readily available in most clinical settings. Therefore, in addition to a detailed medical history (Myers et al. 2013), systematic evaluation of craniofacial morphology (Friedman et al. 2004; Lee et al. 2009) and standard PSG, further studies are needed to determine the optimum office procedure for evaluating the severity and localization of UA occlusion during obstructive events. Ultrasonography is a simple dynamic imaging modality that can reveal most anatomic structures surrounding the UA. Tongue base thickness (TBT) can also be measured in real time by placing the transducer on the
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submental skin surface in a coronal or sagittal plane (Singh et al. 2010). Although cine MRI and ultrafast CT can also record airway changes, they are limited by their availability and are improper for prolonged observation, and accordingly, they cannot be widely used in the clinical setting. Because ultrasound is widely available, non-invasive, radiation free, portable and inexpensive, it is increasingly used by various medical specialties in diverse clinical situations, including diagnostic, procedural guidance and screening applications (Moore and Copel 2011). Previous comparisons of airway anatomic parameters measured by ultrasound, CT (Prasad et al. 2011) and MRI (Liu et al. 2007) have also confirmed the reliability of ultrasound technique. The aim of this study was to use a point-of-care submental ultrasound measuring technique to compare dynamic TBT in patients with and without OSA. The potential role of ultrasound imaging in the diagnostic workup and research of patients with OSA was explored by correlating ultrasound measurements with PSG parameters that indicate the existence of OSA. METHODS Patients The recruitment criteria for the OSA group were recent diagnosis of sleep apnea and an apnea hypopnea index (AHI) $5 episodes/h of sleep, confirmed by standard PSG. No patients had received prior treatment for OSA. The OSA group was recruited from the sleep clinic of Cardinal Tien Hospital. Control patients were recruited from either the clinic or the community. The recruitment criteria for control patients were no history of sleep apnea and an AHI ,5 episodes/h of sleep based on standard PSG. Potential controls presenting with unrecognized symptoms of sleep-disordered breathing and an AHI $5 episodes/h were classified as OSA patients. Potential OSA patients presenting with snoring and an AHI ,5 episodes/h were classified as controls. Other exclusion criteria were refusal to participate, age ,20 y and any history of syndromal craniofacial abnormalities (e.g., Down syndrome); oral cavity, oropharyngeal or laryngeal masses; craniofacial surgery; burns, trauma or radiotherapy involving the head and neck region; neurologic disorders other than OSA; active inflammation in the head and neck region; and cervical rigidity that limited neck flexion and head extension. The institutional review board confirmed that adequate written informed consent was received from all participants. Polysomnography All participants underwent full-night standard PSG (Embla N7000, Medcare, Iceland) in the sleep laboratory according to the OSA diagnosis and management
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guidelines (Epstein et al. 2009). The PSG included continuous recordings of neurologic variables by electroencephalography, electrooculography and surface submentalis electromyography; scoring of breathing variables based on a flow tracing from an oronasal cannula and thermistor; measurement of thoraco-abdominal motion and sleep position using chest and abdominal bands and a position monitor; recording of oxyhemoglobin saturation with a finger pulse oximeter; and electrocardiography. Polysomnograms were scored by registered sleep technologists and were reviewed by certified sleep physicians according to the criteria of Rechtschaffen and Kales (1968) and the updated scoring guidelines provided by the American Academy of Sleep Medicine (American Academy of Sleep Medicine Task Force 1999; Kushida et al. 2005). The sleep technologists and sleep physicians who analyzed the sleep studies were blinded to the ultrasound results. Obstructive apnea was defined as complete cessation of airflow or a $90% reduction in the peak thermal sensor signal for at least 10 s; a hypopnea episode was defined as $50% reduction in the nasal pressure signal for at least 10 s in association with oxyhemoglobin desaturation $3% and/or arousal (American Academy of Sleep Medicine Task Force 1999; Kushida et al. 2005).
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SSA-550A (Toshiba Medical Systems, Otawara, Japan) and a Toshiba PVM-375AT 6-3 MHz curvilinear transducer in gray-scale 2-D mode. The measurements were taken with the subject lying in the supine position on the examination couch, with the neck slightly flexed and head extended with a soft pad under the neck to expose the submental region (inset, Fig. 1). The midline sagittal plane of the tongue base was scanned with the transducer placed on the submental skin of the neck, between the hyoid bone and the symphysis of the mandible. The dorsal surface of the tongue base had a curvilinear hyper-echoic appearance because of the air– mucosa interface. The sonographer may tilt the transducer slightly aside to search the hyper-echoic raphe of the tongue, which is the landmark of the midline septum of the tongue. Vibration artifacts that were occasionally produced when patients swallowed helped to confirm the location of the laryngopharynx. The transforming shape of the tongue base was viewed dynamically with gray-scale real-time ultrasound. The patient was first instructed to remain still and silent during the measurements and to breathe normally and avoid tongue movement, swallowing or talking. The maximum distance between the submental skin and the dorsal surface of the tongue base, TBT (eupneic), and subcutaneous fat thickness, SFT (eupneic), were recorded and measured
Anthropometric measurements Demographic data, including age, gender, weight (kilograms), body height (centimeters) and neck circumference (NC), were recorded by a trained assistant in the sleep clinic. Weight and height were recorded with the patients wearing light clothes, but no shoes. Body mass index (BMI) was then calculated as weight (kg) divided by height squared (m2). NC was measured (in cm) with a flexible tape at the level of the cricothyroid membrane after a gentle expiration by the subject while standing upright. History of hypertension, diabetes, hyperlipidemia or any other cardiovascular diseases was recorded according to medical records or statements by the patients. All participants were asked to complete the validated Chinese version of the Epworth Sleepiness Scale (ESS) (Peng et al. 2011), a subjective self-reported measure of excessive daytime sleepiness, within the same session before the ultrasound examination. Ultrasonographic measurements All measurements were made by a single researcher (C.H.C.), a head and neck surgeon and also a certified sonographer with experience in ultrasound scanning of the head and neck region. The examiner was blinded to the PSG results when performing the ultrasound examination. All submental ultrasound procedures were performed identically in controls and apneic patients. All ultrasound examinations were performed with a Nemio
Fig. 1. Representative sonographic image of submental midline sagittal section. Inset: Transducer position. The dorsal surface of the tongue base had a curvilinear hyper-echoic appearance because of an air-mucosa interface (black arrows). The maximum distance between the submental skin and the dorsal surface of the tongue base was recorded and measured on frozen ultrasound images at the end of expiration during eupneic breathing (tongue base thickness [TBT], white line with double arrows, 51.3 mm in this image). Also seen are two acoustic shadows (AS), reflecting the body of the mandible (M) and hyoid bone (H). MH 5 mylohyoid muscle; GH 5 geniohyoid muscle; GG 5 genioglossus muscle; SLF 5 sublingual fat.
Tongue base thickness in obstructive sleep apnea d J.-W. CHEN et al.
on frozen ultrasound images at the end of expiration during eupneic breathing. The subject was then asked to perform the MM several times; with the examiner lightly pinching the nasal alae to increase airway resistance, the patient attempted to breathe in with the mouth closed. The negative pressure generated by the maneuver caused a narrowing of the upper airway segments most susceptible to collapse during apnea. The varying shape of the tongue base during the MM was again observed dynamically by gray-scale real-time ultrasound. The TBT and SFT were recorded and measured on frozen ultrasound images on performance of the MM with the tongue base positioned farthest away from the transducer (i.e., with the pharyngeal airway presumably decreased to its smallest caliber). The maximum TBT and SFT on the MM were measured three times on three separate images, and the mean values, TBT (MM) and SFT (MM), were obtained for analysis. The difference in TBT, TBT (difference), on eupneic breathing and the MM was defined as TBT (MM) – TBT (eupneic). The difference in SFT, SFT (difference), on eupneic breathing and the MM was defined as SFT (MM) – SFT (eupneic). TBT (difference) and SFT (difference) were computed for each subject for further analysis. Ultrasound measurements for all patients were performed in an examining room in the same area of the sleep clinic within 2 wk before sleep studies. Statistical analysis Results are presented as the mean 6 standard deviation (SD) for continuous variables and as percentages for categorical variables. The Mann–Whitney U-test or c2 Fisher exact test were used as appropriate to compare ultrasound measurements and anthropometric data between controls (AHI ,5 episodes/h) and OSA patients (AHI $5 episodes/h). Logistic regression analyses were performed to identify ultrasound measurements that indicated a risk of OSA. Multivariate models were established after adjustment for potential confounding effects of age, gender, BMI, NC and a history of hyperlipidemia. Weight was not included as a covariate in this model because of its correlation with BMI. The results were summarized as crude and adjusted odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Data were analyzed using IBM SPSS Statistics Version 20.0 software (IBM, Armonk, NY, USA). All reported p-values were two-sided, and a p-value ,0.05 was considered to indicate statistical significance. RESULTS Characteristics of the study population The 40 patients (13 females and 27 males, age range: 24–69 y) recruited for this study included 20 patients with
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OSA and 20 participants with AHI ,5 episodes/h as a control group. Table 1 compares the clinical, anthropometric and polysomnographic data between patients with and those without OSA. The OSA group had significantly higher weight, higher BMI and higher prevalence of hyperlipidemia. Age, gender, body height, NC, ESS score and prevalence of hypertension, diabetes and other cardiovascular diseases did not significantly differ between the two groups. As expected, the OSA patients had a significantly higher AHI and a significantly lower SpO2 nadir compared with controls. Ultrasonographic images Ultrasound imaging reliably revealed the anatomic structures of the tongue and distinguished between fatty tissue, muscle and mucosa. Figure 1 details the anatomy of the midline sagittal section of the tongue as revealed by ultrasound. The tongue was visualized to the depth of the muscles of the mouth floor, that is, the mylohyoid and geniohyoid muscles. The dorsal mucosal surface of the tongue base had a curvilinear hyper-echoic appearance resulting from the air–mucosa interface. Intraluminal air was a poor ultrasound medium and did not allow visualization of deeper structures. The intrinsic muscles of the tongue had a striated appearance on ultrasound. The ultrasound image of the genioglossus muscle, one of the four major extrinsic muscles of the tongue, revealed that it extended in a fanlike fashion to the dorsal surface of the tongue. The exception was the most Table 1. Clinical, anthropometric and polysomnographic characteristics of the study population* Characteristic
Control
OSA
Number of patients 20 20 Age, y 43 6 13 (24–69) 43 6 11 (27–63) Females/males 7/13 6/14 Weight (kg) 71.2 6 11.3 81.7 6 10.3 Body height (cm) 168.6 6 9.6 168.3 6 9.4 24.9 6 2.5 28.9 6 3.2 Body mass index (kg/m2) Neck circumference 39.3 6 3.6 41.4 6 3.8 (cm) Hypertension 4 (20%) 8 (40%) Diabetes 2 (10%) 2 (10%) Hyperlipidemia, n (%) 1 (5%) 7 (35%) Cardiovascular disease, 2 (10%) 2 (10%) n (%) ESS, mean (range) 6.3 (0–14) 8.0 (2–16) AHI, episodes/h Mean 3.0 6 1.9 35.8 6 27.1 Median 3.8 (0.9–4.7) 26.3 (14.2–55.7) Range 0–4.9 7.0–98.6 88 6 2 78 6 9 SpO2 nadir, %
p-Value 1 0.968 0.736 0.004 0.914 ,0.001 0.076 0.168 1 0.044 1 0.213 ,0.001 ,0.001 ,0.001 ,0.001
ESS 5 Epworth Sleepiness Scale; OSA 5 obstructive sleep apnea; SpO2 5 peripheral capillary oxygen saturation. * All data are expressed as the mean 6 standard deviation, number (percentage) or median (interquartile range), unless otherwise specified. p-Values refer to Mann–Whitney U-test or c2 Fisher’s exact test differences between patients with and without obstructive sleep apnea.
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anterior part of the tongue, which was obscured by the acoustic shadow caused by the body of the mandible (Kundra et al. 2011; Lahav et al. 2009; Singh et al. 2010). The other three extrinsic muscles of the tongue, that is, the hyoglossus, styloglossus and palatoglossus muscles, were not visible in the midline sagittal section of the tongue on ultrasound. Figures 2 and 3 comprise representative ultrasound images of controls and OSA patients during eupneic breathing and with the MM, respectively.
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NC and history of hyperlipidemia, significant independent predictors of OSA were TBT measured by ultrasound with the MM (OR 5 2.11, 95% CI: 1.15–3.87, p , 0.05) and difference between TBT with the MM and that without the MM (OR 5 2.47, 95% CI: 1.09– 5.58, p , 0.05). Although weight was found to be significantly higher in the OSA group, it was not included as a covariate in the regression analyses to avoid multicollinearity. DISCUSSION
Ultrasonographic measurements Table 2 summarizes the ultrasound parameters. Compared with controls, OSA patients had significantly higher ultrasound TBT measurements during eupneic breathing (65.5 6 5.1 mm vs. 62.1 6 4.5 mm, p 5 0.037) and with the MM (69.0 6 4.4 mm vs. 63.4 6 6.1 mm, p 5 0.002) and a significantly greater difference between TBT with the MM and that without the MM (3.5 6 2.5 mm vs. 1.2 6 3.4 mm, p 5 0.018). Ultrasound measurements of SFT with and without the MM did not differ between OSA patients and controls. Logistic regression analyses of these ultrasound parameters revealed that after adjustment for age, gender, BMI,
This study of an Asian population confirms that differences in dynamic TBT between patients with and without OSA can be identified by a point-of-care submental ultrasound measuring technique. Ultrasound measurement of TBT with the MM and the difference between TBT with the MM and that without the MM were significantly greater in OSA patients than in controls and were independent of age, gender, BMI, NC and hyperlipidemia. Additionally, the TBT measured by ultrasound at the end of expiration during eupneic breathing was not an independent predictor of OSA after adjustment for confounding factors. These results suggest that ‘‘dynamic’’ imaging modalities, which could partly
Fig. 2. Dynamic changes in tongue base thickness (TBT) in the sonographic images of the controls with and without the Mueller maneuver (MM). The black arrows indicate the curvilinear hyper-echoic stripe of the dorsal surface of the tongue base caused by the air–mucosa interface. Top row (a 1 b): Ultrasound images of a representative female control subject; the maximum distance between the submental skin and the dorsal surface of the tongue base (TBT, white line with double arrows) decreased from 62.3 mm on eupneic breathing (a) to 61.8 mm with the MM (b). Bottom row (c 1 d): Ultrasound images of a representative male control subject; TBT decreased from 66.5 mm on eupneic breathing (c) to 60.7 mm with the MM (d). M 5 mandible; H 5 hyoid bone.
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Fig. 3. Dynamic changes in tongue base thickness (TBT) in the sonographic images of patients with obstructive sleep apnea (OSA) with and without the Mueller maneuver (MM). The black arrows indicate the curvilinear hyper-echoic stripe of the dorsal surface of the tongue base caused by the air–mucosa interface. Top row (a, b): Ultrasound images of a representative female OSA patient; the maximum distance between the submental skin and the dorsal surface of the tongue base (TBT, white line with double arrows) increased from 60.7 mm (a, measured at the end of an expiration during eupneic breathing) to 66.5 mm with the MM (b). Bottom row (c, d): Ultrasound images of a representative male OSA patient; the TBT increased from 62.8 mm on eupneic breathing (c) to 69.6 mm with the MM (d). M 5 mandible; H 5 hyoid bone.
reflect the combined effects of anatomic and neuromuscular abnormalities of the UA during wakefulness, are better clinical tools for evaluating OSA patients than ‘‘static’’ alternatives.
Table 2. Key ultrasonographic results* Ultrasound measurement TBT (eupneic), mm TBT (MM), mm TBT (difference), mm SFT (eupneic), mm SFT (MM), mm SFT (difference), mm
Control
OSA
p-Value
62.1 6 4.5 63.4 6 6.1 1.2 6 3.4 5.2 6 1.3 4.9 6 1.3 20.31 6 0.85
65.5 6 5.1 69.0 6 4.4 3.5 6 2.5 5.6 6 1.3 5.4 6 1.4 20.17 6 0.65
0.037 0.002 0.018 0.416 0.223 0.978
OSA 5 obstructive sleep apnea; SFT 5 subcutaneous fat thickness; TBT 5 tongue base thickness; TBT (eupneic) 5 maximum distance between the submental skin and the dorsal surface of the tongue base on expiration during eupneic breathing; TBT (MM) 5 average of three measurements of the maximum distance between the submental skin and the dorsal surface of the tongue base on the Mueller maneuver; TBT (difference) 5 TBT (MM) 2 TBT (eupneic); SFT (eupneic) 5 SFT on expiration during eupneic breathing; SFT (MM) 5 average of three measurements of SFT on the Mueller maneuver; SFT (difference) 5 SFT (MM) – SFT (eupneic). * Values are expressed as the mean 6 standard deviation. p-Values refer to Mann–Whitney U-test differences between patients with and without obstructive sleep apnea.
Tongue base dynamics during respiration and the Mueller maneuver In our study, real-time ultrasound imaging of the curvilinear part of the tongue base during eupneic breathing also revealed a small but noticeable sinusoidal movement in both controls and OSA patients. This fine movement may depict an interactive balance of forces between muscle tone and passive mechanical load in patients breathing quietly. Under overt negative intraluminal airway pressure, however, the balance of forces was disturbed. The reaction of UA dilator muscles in compensation for the imbalance of forces then revealed a segmental change in the size and shape of the tongue base on ultrasound. The regional tongue movement represents an adaptive activation of a specific neuromuscular compartment of the genioglossus muscles to cope with local negative airway pressure (Brown et al. 2013). We hypothesize that as the severity of sleep-disordered breathing progresses, the mechanical load increases, and a blunted neuromuscular reflex and/or motor neuropathy of the UA dilator muscles occurs. This causes a poorly coordinated response to negative airway pressure during wakefulness, which then causes the tongue base to descend into the pharyngeal airway, followed by collapse of the
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airway. Ultrasound observation of this maladaptive movement of the tongue revealed that the posterior displacement of the tongue base measured by ultrasound on the MM and the difference between TBT with the MM and that without the MM were both greater in OSA patients than in controls. In contrast, the ‘‘static’’ ultrasound measurement in this study, which may only reflect the passive mechanical load, was greater in the OSA patients in the primary analysis (Table 2), whereas it did not significantly differ after adjustment for other obesity measures (Table 3). These statistical results confirm that dynamic TBT in response to negative airway pressure as measured by ultrasound when incorporating the MM, not the absolute dimension of the tongue base recorded during quiet breathing, has a major role in the pathogenesis of OSA. This finding is also consistent with the basic concept that OSA is a multifactorial derangement involving anatomic and neuromuscular abnormalities. For example, only one-third of the variability in severity is attributable to increased mechanical load; two-thirds is attributable to compromised compensatory effectiveness in neuromuscular control (Younes 2003). Ultrasonographic measuring techniques Ultrasonography is becoming a useful adjunct to clinical methods for bedside airway monitoring. The feasibility of ultrasound as an imaging tool for identifying important airway anatomic structures was confirmed in an earlier observational study (Singh et al. 2010). This study used a curved low-frequency transducer because of its wide field of view, which facilitates morphologic study of the entire tongue base. The increased penetration depth also allows better visualization of deeper structures in the floor of the mouth, especially in some obese OSA patients. The midsagittal scanning plane was considered the Table 3. Logistic regression contributors of ultrasound measurements to the existence of OSA* Ultrasound measurement TBT (eupneic), mm TBT (MM), mm TBT (difference), mm
Crude OR (95% CI)
Adjustedy OR (95% CI)
1.18 (0.99–1.40) 1.34 (1.08–1.67)z 1.37 (1.03–1.83)z
1.15 (0.80–1.59) 2.11 (1.15–3.87)z 2.47 (1.09–5.58)z
CI 5 confidence interval; OR 5 odds ratio; OSA 5 obstructive sleep apnea; TBT 5 tongue base thickness; TBT (eupneic) 5 maximum distance between the submental skin and the dorsal surface of the tongue base on expiration during eupneic breathing; TBT (MM) 5 average of three measurements of the maximum distance between the submental skin and the dorsal surface of the tongue base on the Mueller maneuver; TBT (difference) 5 TBT (MM) – TBT (eupneic). * The results of logistic regression analyses were summarized as crude and adjusted odds ratios (OR) with the corresponding 95% confidence intervals (CI). y Adjustments were performed for age, gender, body mass index, neck circumference and hyperlipidemia. z p , 0.05.
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optimum location because it provides the largest acoustic window for observing the motion of the entire tongue base during respiration and negative airway pressure. Tongue base thickness measured by ultrasound is supposed to be correlated negatively with the extent of UA caliber during examination. In an air-containing space deep in the surface of the tongue, air artifacts such as comet tail and reverberation artifacts are identifiable. However, intraluminal air prevented visualization of deep structures such as the posterior pharyngeal wall and arytenoid cartilage. Ultrasonographic measurements in OSA Strong evidence indicates that obesity is a causal factor in OSA (Young et al. 2004). Although NC is considered a better predictor of OSA compared with overall obesity (Davies and Stradling 1990), it remains uncertain which anatomic structures of the neck are most relevant to the pathogenesis of OSA. Several studies have used ultrasound imaging to identify anatomic factors predisposing to OSA. However, most have investigated only anatomic mechanisms, which may explain the inconsistency in the observed results. Lateral pharyngeal wall thickness was identified as a major cause of OSA in an MRI study (Schwab et al. 1995). Compared with a measurement of lateral pharyngeal wall thickness by MRI, a measurement obtained by ultrasound is reliable and is also found to correlate with the severity of OSA (Liu et al. 2007). An earlier study found that the distance between lingual arteries, a surrogate measure of tongue base width, as acquired by Doppler mode ultrasound in submental coronal section, correlates with the occurrence and severity of OSA (Lahav et al. 2009). However, although maximal tongue height was measured, the authors failed to find a significant difference between control patients and OSA patients (Lahav et al. 2009). Another study (Ugur et al. 2011) used ultrasound to investigate the thickness of SFT in the neck and umbilicus in OSA patients and reported no significant correlation between polysomnographic findings and ultrasound measurements. SFT measured with ultrasound in our study also did not differ between OSA patients and controls. In a pilot study (Siegel et al. 2000), ultrasound examination of the pharynx was synchronized with PSG in five OSA patients during sleep and revealed that all apneic events identified by PSG were accompanied by an ultrasound event, which indicated preceding relaxation of the floor of mouth muscle before the onset of apnea, followed by posterior and inferior displacement of the tongue base toward the laryngopharynx during apnea. Notably, the characteristic feature of the ultrasound events was consistent for each subject and was observed in all samples. They concluded that ultrasound is a simple, dynamic and non-invasive clinical tool for visualizing the airway and has strong potential for use in diagnosis, treatment and prognosis of OSA.
Tongue base thickness in obstructive sleep apnea d J.-W. CHEN et al.
With the help of a miniature surface transducer, signal and image processing modules, image display and data storage units, monitoring of OSA patients’ retroglossal airways with ultrasound has the potential to be incorporated into polysomnography and to provide information about retroglossal airway behavior during natural sleep, which is very important in devising, applying and determining the effectiveness of tailor-made treatment modalities. Limitations of the study This study has several limitations. First, some of the control patients in this study had a higher than normal risk for OSA because they were recruited from a sleep clinic population. Morphologically, these control patients were more similar to OSA patients than to control patients selected from community populations. However, this suggests that this study likely underestimated the true differences. Second, the correlation between dynamic TBT measured by ultrasound and that measured by other more established imaging modalities (CT or MRI) was not tested because the patients had difficulty maintaining the MM during the prolonged scanning time of conventional CT or MRI. Further studies are needed specifically to validate the reliability of the dynamic ultrasound measuring technique by comparing it with ultrafast CT or cine MRI. Additionally, a pharyngeal pressure monitor was not used to record the effects of the MM. However, all patients were asked to practice the MM before examination, and three distinct measurements were used for the calculation to improve the reliability of this maneuver. Additional limitations of the ultrasound measuring technique include possible errors in subject alignment or probe position and arbitrary determination of the dimensions of the tongue base by the examiner. Although these issues may affect the accuracy of the technique, they can be minimized by a study design in which a standard procedure is used and in which a single operator performs all ultrasound examinations. Furthermore, this study did not investigate the reproducibility of ultrasound measurement. However, previous studies (Liu et al. 2007; Shu et al. 2013) confirmed that ultrasound measurements in the neck region had high intra-operator and interoperator reliability. Overall, the study populations had low ESS and BMI scores, which might indicate a milder form of the disease, and some patients were minimally symptomatic. However, this may have resulted from the lower obesity rate in Asian OSA patients compared with their Caucasian counterparts despite their similar prevalence rates of OSA. CONCLUSIONS Upper airway anatomy is fundamentally important in OSA pathogenesis. However, interacting effects of
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the abnormal neuromuscular control mechanism of the upper airway dilator muscle and other pathophysiologic factors such as respiratory arousal threshold and loop gain make OSA a multifactorial disease. Recent observations of tongue movement during quiet inspiration have revealed that OSA patients might have impaired respiratory control even when awake. This study developed a submental ultrasound technique for quantifying UA behavior in response to negative airway pressure while the subject is awake. Independent predictors of OSA included TBT measured by ultrasound with the MM and the difference between TBT with the MM and that without the MM. Submental ultrasound measurement of TBT with the MM is an alternative objective clinical modality for easy and tolerable evaluation of potential patterns and severity of airway obstruction in OSA patients while they are awake. Acknowledgments—The authors are grateful for technical support on this project provided by Chiu-Ping Wang and Shu-Hwei Fan. The authors also express their gratitude to all of the staff of the Center of Sleep Disorders and Division of Pulmonary Medicine of Cardinal Tien Hospital. Ted Knoy is appreciated for his editorial assistance. This research was supported by the National Science Council (NSC) of Taiwan (Project Grant NSC 102-2628-B-030-001-MY3).
REFERENCES American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: Recommendations for syndrome definition and measurement techniques in clinical research. The report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667–689. Arens R, Marcus CL. Pathophysiology of upper airway obstruction: A developmental perspective. Sleep 2004;27:997–1019. Brown EC, Cheng S, McKenzie DK, Butler JE, Gandevia SC, Bilston LE. Respiratory movement of upper airway tissue in obstructive sleep apnea. Sleep 2013;36:1069–1076. Davidson TM. The Great Leap Forward: The anatomic basis for the acquisition of speech and obstructive sleep apnea. Sleep Med 2003;4:185–194. Davidson TM, Sedgh J, Tran D, Stepnowsky CJ Jr. The anatomic basis for the acquisition of speech and obstructive sleep apnea: Evidence from cephalometric analysis supports The Great Leap Forward hypothesis. Sleep Med 2005;6:497–505. Davies RJ, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990;3:509–514. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD. Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263–276. Faber CE, Grymer L. Available techniques for objective assessment of upper airway narrowing in snoring and sleep apnea. Sleep Breath 2003;7:77–86. Friedman M, Ibrahim H, Joseph NJ. Staging of obstructive sleep apnea/ hypopnea syndrome: A guide to appropriate treatment. Laryngoscope 2004;114:454–459. Horner RL. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 1996; 19:827–853. Kajee Y, Pelteret JP, Reddy BD. The biomechanics of the human tongue. Int J Numer Method Biomed Eng 2013;29:492–514.
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Kundra P, Mishra SK, Ramesh A. Ultrasound of the airway. Indian J Anaesth 2011;55:456–462. Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J Jr, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Loube DL, Owens J, Pancer JP, Wise M. Practice parameters for the indications for polysomnography and related procedures: An update for 2005. Sleep 2005;28:499–521. Lahav Y, Rosenzweig E, Heyman Z, Doljansky J, Green A, Dagan Y. Tongue base ultrasound: A diagnostic tool for predicting obstructive sleep apnea. Ann Otol Rhinol Laryngol 2009;118:179–184. Lee RW, Chan AS, Grunstein RR, Cistulli PA. Craniofacial phenotyping in obstructive sleep apnea—A novel quantitative photographic approach. Sleep 2009;32:37–45. Liu KH, Chu WC, To KW, Ko FW, Tong MW, Chan JW, Hui DS. Sonographic measurement of lateral parapharyngeal wall thickness in patients with obstructive sleep apnea. Sleep 2007;30:1503–1508. Moore CL, Copel JA. Point-of-care ultrasonography. N Engl J Med 2011;364:749–757. Myers KA, Mrkobrada M, Simel DL. Does this patient have obstructive sleep apnea?: The Rational Clinical Examination systematic review. JAMA 2013;310:731–741. Peng LL, Li JR, Sun JJ, Li WY, Sun YM, Zhang R, Yu LL. [Reliability and validity of the simplified Chinese version of Epworth Sleepiness Scale]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2011;46: 44–49. Prasad A, Yu E, Wong DT, Karkhanis R, Gullane P, Chan VW. Comparison of sonography and computed tomography as imaging tools for assessment of airway structures. J Ultrasound Med 2011;30: 965–972. Rama AN, Tekwani SH, Kushida CA. Sites of obstruction in obstructive sleep apnea. Chest 2002;122:1139–1147. Rechtschaffen A, Kales A. A manual of standardized terminology and scoring system for sleep stages of human patients. Los Angeles:
Volume 40, Number 11, 2014 Brain Information Service/Brain Research Institute, University of California at Los Angeles; 1968. Schwab RJ, Gupta KB, Gefter WB, Metzger LJ, Hoffman EA, Pack AI. Upper airway and soft tissue anatomy in normal patients and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152:1673–1689. Shepard JW Jr, Gefter WB, Guilleminault C, Hoffman EA, Hoffstein V, Hudgel DW, Suratt PM, White DP. Evaluation of the upper airway in patients with obstructive sleep apnea. Sleep 1991;14:361–371. Shu CC, Lee P, Lin JW, Huang CT, Chang YC, Yu CJ, Wang HC. The use of sub-mental ultrasonography for identifying patients with severe obstructive sleep apnea. PLoS One 2013;8:e62848. Siegel H, Sonies BC, Graham B, McCutchen C, Hunter K, Vega-Bermudez F, Sato S. Obstructive sleep apnea: A study by simultaneous polysomnography and ultrasonic imaging. Neurology 2000;54:1872. Singh M, Chin KJ, Chan VW, Wong DT, Prasad GA, Yu E. Use of sonography for airway assessment: An observational study. J Ultrasound Med 2010;29:79–85. Stuck BA, Maurer JT. Airway evaluation in obstructive sleep apnea. Sleep Med Rev 2008;12:411–436. Togeiro SM, Chaves CM Jr, Palombini L, Tufik S, Hora F, Nery LE. Evaluation of the upper airway in obstructive sleep apnoea. Indian J Med Res 2010;131:230–235. Ugur KS, Ark N, Kurtaran H, Kizilbulut G, Cakir B, Ozol D, Gunduz M. Subcutaneous fat tissue thickness of the anterior neck and umbilicus in patients with obstructive sleep apnea. Otolaryngol Head Neck Surg 2011;145:505–510. Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med 2003;168:645–658. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004;291:2013–2016.
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.06.019
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Original Contribution SUBMENTAL ULTRASOUND MEASUREMENT OF DYNAMIC TONGUE BASE THICKNESS IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA JENG-WEN CHEN,*y CHUN-HSIANG CHANG,*y SHOU-JEN WANG,*y YEN-TEH CHANG,yz and CHIH-CHUNG HUANGx * Department of Otolaryngology Head and Neck Surgery, Cardinal Tien Hospital, New Taipei City, Taiwan; y School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; z Division of Pulmonary Medicine, Department of Internal Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan; and x Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan (Received 30 April 2014; revised 10 June 2014; in final form 30 June 2014)
Abstract—Dynamic tongue base thickness (TBT) may be an important anatomic factor in airway narrowing in patients with obstructive sleep apnea (OSA). The development of an accurate clinical assessment of the retroglossal airway in patients with OSA is still evolving. Submental ultrasound was used to investigate the association between measurements of TBT in response to negative airway pressure and the existence of OSA. Twenty OSA patients and 20 control participants underwent ultrasound measurement of TBT on eupneic breathing and with the Mueller maneuver, as well as clinical and polysomnographic assessments. Logistic regression analyses indicated that after adjustment for confounding factors, independent predictors of OSA included TBT in response to negative airway pressure, as measured by submental ultrasound with the Mueller maneuver (odds ratio: 2.11, 95% confidence interval: 1.15–3.87, p , 0.05), and the difference between TBT with the Muller maneuver and that without the Mueller maneuver (odds ratio: 2.47, 95% confidence interval: 1.09–5.58, p , 0.05). Ultrasound measurement of TBT during the Mueller maneuver provides a quantitative assessment of the retroglossal airway in OSA patients with minimal invasiveness and easy accessibility. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Obstructive sleep apnea, Ultrasound, Tongue base thickness, Mueller maneuver, Polysomnography.
physiologic effects of these respiratory events, even attended, laboratory-based PSG cannot precisely localize the sites of upper airway (UA) occlusion. Therefore, additional clinical tools for evaluating static and/or dynamic UA anatomy are needed not only for improved understanding of the biomechanics and pathophysiology of OSA, but also for improved patient management and treatment success. The oropharynx, with extension to the laryngopharynx, is the major anatomic location in which airway collapse occurs (Horner 1996; Rama et al. 2002). Obstructive sleep apnea is hypothesized to have resulted from specific evolutionary changes in the human UA that facilitate speech and language development. These changes cause posterior migration of the tongue base on the laryngeal aperture and considerable narrowing of the pharyngeal airway (Davidson 2003; Davidson et al. 2005). The human tongue is a highly mobile organ with interweaving but distinct skeletal muscle groups. A biomechanical analysis of the human tongue has been
INTRODUCTION Obstructive sleep apnea (OSA), a breathing disorder characterized by recurring episodes of partial or complete obstruction of the pharyngeal airway during sleep, can cause intermittent hypoxemia, frequent arousal and sleep fragmentation (Arens and Marcus 2004). Patients are often referred to health care professionals by concerned bed partners or parents who have witnessed apneas followed by snoring, choking or gasping (Myers et al. 2013). The diagnosis of OSA syndrome is based on clinical symptoms and episodes of apnea and hypopnea measured by polysomnography (PSG). Although PSG is the gold standard for diagnosing OSA and for recording
Address correspondence to: Chih-Chung Huang, Department of Biomedical Engineering, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan. E-mail: cchuang@mail. ncku.edu.tw Conflicts of Interest: This was not an industry-supported study. The authors have indicated no financial conflicts of interest. 2590
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performed with a geometric constitutive model (Kajee et al. 2013). Computational simulations based on this model have indicated that, even without active muscle contraction, these interwoven muscle fibers generate sufficient stiffness to partially overcome the gravitational forces when in the supine position. Only a select group of muscles must work simultaneously for efficient prevention of posterior displacement of the tongue base and, thus, airway collapse. This hypothesis was further tested in a recent study by Brown et al. (2013), who used a tagged cine magnetic resonance imaging technique to compare UA soft tissue mechanics during respiration in OSA patients and normal patients. They reported that patients with severe OSA usually exhibit minimal tongue movement during quiet breathing because of their difficulty dilating the restricted UA even in wakefulness. Several imaging modalities including X-ray cephalometry, computed tomography (CT) scanning and magnetic resonance imaging (MRI), have been used to analyze ‘‘static’’ predisposing factors in the UA anatomy of OSA patients while awake and while asleep. Numerous ‘‘dynamic’’ techniques such as ultrafast CT scanning, cine MRI, pressure measurements, fluoroscopy and acoustic reflections have also been used specifically to identify the severity of UA obstruction in OSA patients. Each method has unique advantages and limitations (Shepard et al. 1991; Faber and Grymer 2003; Stuck and Maurer 2008; Togeiro et al. 2010), which may explain the wide variation in the reported results. Together, these techniques for UA assessment have substantially improved the understanding of OSA. However, their use in daily practice is still limited. In contrast, other routinely used clinical tools such as cephalometry, fiberoptic nasopharyngoscopy with the Mueller maneuver (MM) and druginduced sleep endoscopy have provided little evidence of improved treatment outcomes (Stuck and Maurer 2008). The MM has been widely applied to simulate the pathophysiologic condition of OSA during wakefulness. Even though limited in subjectivity and nonquantitative, fiberoptic nasopharyngoscopy with the MM remains one of the most commonly used office procedures for evaluating UA in OSA patients. Other sophisticated imaging modalities are not readily available in most clinical settings. Therefore, in addition to a detailed medical history (Myers et al. 2013), systematic evaluation of craniofacial morphology (Friedman et al. 2004; Lee et al. 2009) and standard PSG, further studies are needed to determine the optimum office procedure for evaluating the severity and localization of UA occlusion during obstructive events. Ultrasonography is a simple dynamic imaging modality that can reveal most anatomic structures surrounding the UA. Tongue base thickness (TBT) can also be measured in real time by placing the transducer on the
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submental skin surface in a coronal or sagittal plane (Singh et al. 2010). Although cine MRI and ultrafast CT can also record airway changes, they are limited by their availability and are improper for prolonged observation, and accordingly, they cannot be widely used in the clinical setting. Because ultrasound is widely available, non-invasive, radiation free, portable and inexpensive, it is increasingly used by various medical specialties in diverse clinical situations, including diagnostic, procedural guidance and screening applications (Moore and Copel 2011). Previous comparisons of airway anatomic parameters measured by ultrasound, CT (Prasad et al. 2011) and MRI (Liu et al. 2007) have also confirmed the reliability of ultrasound technique. The aim of this study was to use a point-of-care submental ultrasound measuring technique to compare dynamic TBT in patients with and without OSA. The potential role of ultrasound imaging in the diagnostic workup and research of patients with OSA was explored by correlating ultrasound measurements with PSG parameters that indicate the existence of OSA. METHODS Patients The recruitment criteria for the OSA group were recent diagnosis of sleep apnea and an apnea hypopnea index (AHI) $5 episodes/h of sleep, confirmed by standard PSG. No patients had received prior treatment for OSA. The OSA group was recruited from the sleep clinic of Cardinal Tien Hospital. Control patients were recruited from either the clinic or the community. The recruitment criteria for control patients were no history of sleep apnea and an AHI ,5 episodes/h of sleep based on standard PSG. Potential controls presenting with unrecognized symptoms of sleep-disordered breathing and an AHI $5 episodes/h were classified as OSA patients. Potential OSA patients presenting with snoring and an AHI ,5 episodes/h were classified as controls. Other exclusion criteria were refusal to participate, age ,20 y and any history of syndromal craniofacial abnormalities (e.g., Down syndrome); oral cavity, oropharyngeal or laryngeal masses; craniofacial surgery; burns, trauma or radiotherapy involving the head and neck region; neurologic disorders other than OSA; active inflammation in the head and neck region; and cervical rigidity that limited neck flexion and head extension. The institutional review board confirmed that adequate written informed consent was received from all participants. Polysomnography All participants underwent full-night standard PSG (Embla N7000, Medcare, Iceland) in the sleep laboratory according to the OSA diagnosis and management
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guidelines (Epstein et al. 2009). The PSG included continuous recordings of neurologic variables by electroencephalography, electrooculography and surface submentalis electromyography; scoring of breathing variables based on a flow tracing from an oronasal cannula and thermistor; measurement of thoraco-abdominal motion and sleep position using chest and abdominal bands and a position monitor; recording of oxyhemoglobin saturation with a finger pulse oximeter; and electrocardiography. Polysomnograms were scored by registered sleep technologists and were reviewed by certified sleep physicians according to the criteria of Rechtschaffen and Kales (1968) and the updated scoring guidelines provided by the American Academy of Sleep Medicine (American Academy of Sleep Medicine Task Force 1999; Kushida et al. 2005). The sleep technologists and sleep physicians who analyzed the sleep studies were blinded to the ultrasound results. Obstructive apnea was defined as complete cessation of airflow or a $90% reduction in the peak thermal sensor signal for at least 10 s; a hypopnea episode was defined as $50% reduction in the nasal pressure signal for at least 10 s in association with oxyhemoglobin desaturation $3% and/or arousal (American Academy of Sleep Medicine Task Force 1999; Kushida et al. 2005).
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SSA-550A (Toshiba Medical Systems, Otawara, Japan) and a Toshiba PVM-375AT 6-3 MHz curvilinear transducer in gray-scale 2-D mode. The measurements were taken with the subject lying in the supine position on the examination couch, with the neck slightly flexed and head extended with a soft pad under the neck to expose the submental region (inset, Fig. 1). The midline sagittal plane of the tongue base was scanned with the transducer placed on the submental skin of the neck, between the hyoid bone and the symphysis of the mandible. The dorsal surface of the tongue base had a curvilinear hyper-echoic appearance because of the air– mucosa interface. The sonographer may tilt the transducer slightly aside to search the hyper-echoic raphe of the tongue, which is the landmark of the midline septum of the tongue. Vibration artifacts that were occasionally produced when patients swallowed helped to confirm the location of the laryngopharynx. The transforming shape of the tongue base was viewed dynamically with gray-scale real-time ultrasound. The patient was first instructed to remain still and silent during the measurements and to breathe normally and avoid tongue movement, swallowing or talking. The maximum distance between the submental skin and the dorsal surface of the tongue base, TBT (eupneic), and subcutaneous fat thickness, SFT (eupneic), were recorded and measured
Anthropometric measurements Demographic data, including age, gender, weight (kilograms), body height (centimeters) and neck circumference (NC), were recorded by a trained assistant in the sleep clinic. Weight and height were recorded with the patients wearing light clothes, but no shoes. Body mass index (BMI) was then calculated as weight (kg) divided by height squared (m2). NC was measured (in cm) with a flexible tape at the level of the cricothyroid membrane after a gentle expiration by the subject while standing upright. History of hypertension, diabetes, hyperlipidemia or any other cardiovascular diseases was recorded according to medical records or statements by the patients. All participants were asked to complete the validated Chinese version of the Epworth Sleepiness Scale (ESS) (Peng et al. 2011), a subjective self-reported measure of excessive daytime sleepiness, within the same session before the ultrasound examination. Ultrasonographic measurements All measurements were made by a single researcher (C.H.C.), a head and neck surgeon and also a certified sonographer with experience in ultrasound scanning of the head and neck region. The examiner was blinded to the PSG results when performing the ultrasound examination. All submental ultrasound procedures were performed identically in controls and apneic patients. All ultrasound examinations were performed with a Nemio
Fig. 1. Representative sonographic image of submental midline sagittal section. Inset: Transducer position. The dorsal surface of the tongue base had a curvilinear hyper-echoic appearance because of an air-mucosa interface (black arrows). The maximum distance between the submental skin and the dorsal surface of the tongue base was recorded and measured on frozen ultrasound images at the end of expiration during eupneic breathing (tongue base thickness [TBT], white line with double arrows, 51.3 mm in this image). Also seen are two acoustic shadows (AS), reflecting the body of the mandible (M) and hyoid bone (H). MH 5 mylohyoid muscle; GH 5 geniohyoid muscle; GG 5 genioglossus muscle; SLF 5 sublingual fat.
Tongue base thickness in obstructive sleep apnea d J.-W. CHEN et al.
on frozen ultrasound images at the end of expiration during eupneic breathing. The subject was then asked to perform the MM several times; with the examiner lightly pinching the nasal alae to increase airway resistance, the patient attempted to breathe in with the mouth closed. The negative pressure generated by the maneuver caused a narrowing of the upper airway segments most susceptible to collapse during apnea. The varying shape of the tongue base during the MM was again observed dynamically by gray-scale real-time ultrasound. The TBT and SFT were recorded and measured on frozen ultrasound images on performance of the MM with the tongue base positioned farthest away from the transducer (i.e., with the pharyngeal airway presumably decreased to its smallest caliber). The maximum TBT and SFT on the MM were measured three times on three separate images, and the mean values, TBT (MM) and SFT (MM), were obtained for analysis. The difference in TBT, TBT (difference), on eupneic breathing and the MM was defined as TBT (MM) – TBT (eupneic). The difference in SFT, SFT (difference), on eupneic breathing and the MM was defined as SFT (MM) – SFT (eupneic). TBT (difference) and SFT (difference) were computed for each subject for further analysis. Ultrasound measurements for all patients were performed in an examining room in the same area of the sleep clinic within 2 wk before sleep studies. Statistical analysis Results are presented as the mean 6 standard deviation (SD) for continuous variables and as percentages for categorical variables. The Mann–Whitney U-test or c2 Fisher exact test were used as appropriate to compare ultrasound measurements and anthropometric data between controls (AHI ,5 episodes/h) and OSA patients (AHI $5 episodes/h). Logistic regression analyses were performed to identify ultrasound measurements that indicated a risk of OSA. Multivariate models were established after adjustment for potential confounding effects of age, gender, BMI, NC and a history of hyperlipidemia. Weight was not included as a covariate in this model because of its correlation with BMI. The results were summarized as crude and adjusted odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Data were analyzed using IBM SPSS Statistics Version 20.0 software (IBM, Armonk, NY, USA). All reported p-values were two-sided, and a p-value ,0.05 was considered to indicate statistical significance. RESULTS Characteristics of the study population The 40 patients (13 females and 27 males, age range: 24–69 y) recruited for this study included 20 patients with
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OSA and 20 participants with AHI ,5 episodes/h as a control group. Table 1 compares the clinical, anthropometric and polysomnographic data between patients with and those without OSA. The OSA group had significantly higher weight, higher BMI and higher prevalence of hyperlipidemia. Age, gender, body height, NC, ESS score and prevalence of hypertension, diabetes and other cardiovascular diseases did not significantly differ between the two groups. As expected, the OSA patients had a significantly higher AHI and a significantly lower SpO2 nadir compared with controls. Ultrasonographic images Ultrasound imaging reliably revealed the anatomic structures of the tongue and distinguished between fatty tissue, muscle and mucosa. Figure 1 details the anatomy of the midline sagittal section of the tongue as revealed by ultrasound. The tongue was visualized to the depth of the muscles of the mouth floor, that is, the mylohyoid and geniohyoid muscles. The dorsal mucosal surface of the tongue base had a curvilinear hyper-echoic appearance resulting from the air–mucosa interface. Intraluminal air was a poor ultrasound medium and did not allow visualization of deeper structures. The intrinsic muscles of the tongue had a striated appearance on ultrasound. The ultrasound image of the genioglossus muscle, one of the four major extrinsic muscles of the tongue, revealed that it extended in a fanlike fashion to the dorsal surface of the tongue. The exception was the most Table 1. Clinical, anthropometric and polysomnographic characteristics of the study population* Characteristic
Control
OSA
Number of patients 20 20 Age, y 43 6 13 (24–69) 43 6 11 (27–63) Females/males 7/13 6/14 Weight (kg) 71.2 6 11.3 81.7 6 10.3 Body height (cm) 168.6 6 9.6 168.3 6 9.4 24.9 6 2.5 28.9 6 3.2 Body mass index (kg/m2) Neck circumference 39.3 6 3.6 41.4 6 3.8 (cm) Hypertension 4 (20%) 8 (40%) Diabetes 2 (10%) 2 (10%) Hyperlipidemia, n (%) 1 (5%) 7 (35%) Cardiovascular disease, 2 (10%) 2 (10%) n (%) ESS, mean (range) 6.3 (0–14) 8.0 (2–16) AHI, episodes/h Mean 3.0 6 1.9 35.8 6 27.1 Median 3.8 (0.9–4.7) 26.3 (14.2–55.7) Range 0–4.9 7.0–98.6 88 6 2 78 6 9 SpO2 nadir, %
p-Value 1 0.968 0.736 0.004 0.914 ,0.001 0.076 0.168 1 0.044 1 0.213 ,0.001 ,0.001 ,0.001 ,0.001
ESS 5 Epworth Sleepiness Scale; OSA 5 obstructive sleep apnea; SpO2 5 peripheral capillary oxygen saturation. * All data are expressed as the mean 6 standard deviation, number (percentage) or median (interquartile range), unless otherwise specified. p-Values refer to Mann–Whitney U-test or c2 Fisher’s exact test differences between patients with and without obstructive sleep apnea.
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anterior part of the tongue, which was obscured by the acoustic shadow caused by the body of the mandible (Kundra et al. 2011; Lahav et al. 2009; Singh et al. 2010). The other three extrinsic muscles of the tongue, that is, the hyoglossus, styloglossus and palatoglossus muscles, were not visible in the midline sagittal section of the tongue on ultrasound. Figures 2 and 3 comprise representative ultrasound images of controls and OSA patients during eupneic breathing and with the MM, respectively.
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NC and history of hyperlipidemia, significant independent predictors of OSA were TBT measured by ultrasound with the MM (OR 5 2.11, 95% CI: 1.15–3.87, p , 0.05) and difference between TBT with the MM and that without the MM (OR 5 2.47, 95% CI: 1.09– 5.58, p , 0.05). Although weight was found to be significantly higher in the OSA group, it was not included as a covariate in the regression analyses to avoid multicollinearity. DISCUSSION
Ultrasonographic measurements Table 2 summarizes the ultrasound parameters. Compared with controls, OSA patients had significantly higher ultrasound TBT measurements during eupneic breathing (65.5 6 5.1 mm vs. 62.1 6 4.5 mm, p 5 0.037) and with the MM (69.0 6 4.4 mm vs. 63.4 6 6.1 mm, p 5 0.002) and a significantly greater difference between TBT with the MM and that without the MM (3.5 6 2.5 mm vs. 1.2 6 3.4 mm, p 5 0.018). Ultrasound measurements of SFT with and without the MM did not differ between OSA patients and controls. Logistic regression analyses of these ultrasound parameters revealed that after adjustment for age, gender, BMI,
This study of an Asian population confirms that differences in dynamic TBT between patients with and without OSA can be identified by a point-of-care submental ultrasound measuring technique. Ultrasound measurement of TBT with the MM and the difference between TBT with the MM and that without the MM were significantly greater in OSA patients than in controls and were independent of age, gender, BMI, NC and hyperlipidemia. Additionally, the TBT measured by ultrasound at the end of expiration during eupneic breathing was not an independent predictor of OSA after adjustment for confounding factors. These results suggest that ‘‘dynamic’’ imaging modalities, which could partly
Fig. 2. Dynamic changes in tongue base thickness (TBT) in the sonographic images of the controls with and without the Mueller maneuver (MM). The black arrows indicate the curvilinear hyper-echoic stripe of the dorsal surface of the tongue base caused by the air–mucosa interface. Top row (a 1 b): Ultrasound images of a representative female control subject; the maximum distance between the submental skin and the dorsal surface of the tongue base (TBT, white line with double arrows) decreased from 62.3 mm on eupneic breathing (a) to 61.8 mm with the MM (b). Bottom row (c 1 d): Ultrasound images of a representative male control subject; TBT decreased from 66.5 mm on eupneic breathing (c) to 60.7 mm with the MM (d). M 5 mandible; H 5 hyoid bone.
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Fig. 3. Dynamic changes in tongue base thickness (TBT) in the sonographic images of patients with obstructive sleep apnea (OSA) with and without the Mueller maneuver (MM). The black arrows indicate the curvilinear hyper-echoic stripe of the dorsal surface of the tongue base caused by the air–mucosa interface. Top row (a, b): Ultrasound images of a representative female OSA patient; the maximum distance between the submental skin and the dorsal surface of the tongue base (TBT, white line with double arrows) increased from 60.7 mm (a, measured at the end of an expiration during eupneic breathing) to 66.5 mm with the MM (b). Bottom row (c, d): Ultrasound images of a representative male OSA patient; the TBT increased from 62.8 mm on eupneic breathing (c) to 69.6 mm with the MM (d). M 5 mandible; H 5 hyoid bone.
reflect the combined effects of anatomic and neuromuscular abnormalities of the UA during wakefulness, are better clinical tools for evaluating OSA patients than ‘‘static’’ alternatives.
Table 2. Key ultrasonographic results* Ultrasound measurement TBT (eupneic), mm TBT (MM), mm TBT (difference), mm SFT (eupneic), mm SFT (MM), mm SFT (difference), mm
Control
OSA
p-Value
62.1 6 4.5 63.4 6 6.1 1.2 6 3.4 5.2 6 1.3 4.9 6 1.3 20.31 6 0.85
65.5 6 5.1 69.0 6 4.4 3.5 6 2.5 5.6 6 1.3 5.4 6 1.4 20.17 6 0.65
0.037 0.002 0.018 0.416 0.223 0.978
OSA 5 obstructive sleep apnea; SFT 5 subcutaneous fat thickness; TBT 5 tongue base thickness; TBT (eupneic) 5 maximum distance between the submental skin and the dorsal surface of the tongue base on expiration during eupneic breathing; TBT (MM) 5 average of three measurements of the maximum distance between the submental skin and the dorsal surface of the tongue base on the Mueller maneuver; TBT (difference) 5 TBT (MM) 2 TBT (eupneic); SFT (eupneic) 5 SFT on expiration during eupneic breathing; SFT (MM) 5 average of three measurements of SFT on the Mueller maneuver; SFT (difference) 5 SFT (MM) – SFT (eupneic). * Values are expressed as the mean 6 standard deviation. p-Values refer to Mann–Whitney U-test differences between patients with and without obstructive sleep apnea.
Tongue base dynamics during respiration and the Mueller maneuver In our study, real-time ultrasound imaging of the curvilinear part of the tongue base during eupneic breathing also revealed a small but noticeable sinusoidal movement in both controls and OSA patients. This fine movement may depict an interactive balance of forces between muscle tone and passive mechanical load in patients breathing quietly. Under overt negative intraluminal airway pressure, however, the balance of forces was disturbed. The reaction of UA dilator muscles in compensation for the imbalance of forces then revealed a segmental change in the size and shape of the tongue base on ultrasound. The regional tongue movement represents an adaptive activation of a specific neuromuscular compartment of the genioglossus muscles to cope with local negative airway pressure (Brown et al. 2013). We hypothesize that as the severity of sleep-disordered breathing progresses, the mechanical load increases, and a blunted neuromuscular reflex and/or motor neuropathy of the UA dilator muscles occurs. This causes a poorly coordinated response to negative airway pressure during wakefulness, which then causes the tongue base to descend into the pharyngeal airway, followed by collapse of the
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airway. Ultrasound observation of this maladaptive movement of the tongue revealed that the posterior displacement of the tongue base measured by ultrasound on the MM and the difference between TBT with the MM and that without the MM were both greater in OSA patients than in controls. In contrast, the ‘‘static’’ ultrasound measurement in this study, which may only reflect the passive mechanical load, was greater in the OSA patients in the primary analysis (Table 2), whereas it did not significantly differ after adjustment for other obesity measures (Table 3). These statistical results confirm that dynamic TBT in response to negative airway pressure as measured by ultrasound when incorporating the MM, not the absolute dimension of the tongue base recorded during quiet breathing, has a major role in the pathogenesis of OSA. This finding is also consistent with the basic concept that OSA is a multifactorial derangement involving anatomic and neuromuscular abnormalities. For example, only one-third of the variability in severity is attributable to increased mechanical load; two-thirds is attributable to compromised compensatory effectiveness in neuromuscular control (Younes 2003). Ultrasonographic measuring techniques Ultrasonography is becoming a useful adjunct to clinical methods for bedside airway monitoring. The feasibility of ultrasound as an imaging tool for identifying important airway anatomic structures was confirmed in an earlier observational study (Singh et al. 2010). This study used a curved low-frequency transducer because of its wide field of view, which facilitates morphologic study of the entire tongue base. The increased penetration depth also allows better visualization of deeper structures in the floor of the mouth, especially in some obese OSA patients. The midsagittal scanning plane was considered the Table 3. Logistic regression contributors of ultrasound measurements to the existence of OSA* Ultrasound measurement TBT (eupneic), mm TBT (MM), mm TBT (difference), mm
Crude OR (95% CI)
Adjustedy OR (95% CI)
1.18 (0.99–1.40) 1.34 (1.08–1.67)z 1.37 (1.03–1.83)z
1.15 (0.80–1.59) 2.11 (1.15–3.87)z 2.47 (1.09–5.58)z
CI 5 confidence interval; OR 5 odds ratio; OSA 5 obstructive sleep apnea; TBT 5 tongue base thickness; TBT (eupneic) 5 maximum distance between the submental skin and the dorsal surface of the tongue base on expiration during eupneic breathing; TBT (MM) 5 average of three measurements of the maximum distance between the submental skin and the dorsal surface of the tongue base on the Mueller maneuver; TBT (difference) 5 TBT (MM) – TBT (eupneic). * The results of logistic regression analyses were summarized as crude and adjusted odds ratios (OR) with the corresponding 95% confidence intervals (CI). y Adjustments were performed for age, gender, body mass index, neck circumference and hyperlipidemia. z p , 0.05.
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optimum location because it provides the largest acoustic window for observing the motion of the entire tongue base during respiration and negative airway pressure. Tongue base thickness measured by ultrasound is supposed to be correlated negatively with the extent of UA caliber during examination. In an air-containing space deep in the surface of the tongue, air artifacts such as comet tail and reverberation artifacts are identifiable. However, intraluminal air prevented visualization of deep structures such as the posterior pharyngeal wall and arytenoid cartilage. Ultrasonographic measurements in OSA Strong evidence indicates that obesity is a causal factor in OSA (Young et al. 2004). Although NC is considered a better predictor of OSA compared with overall obesity (Davies and Stradling 1990), it remains uncertain which anatomic structures of the neck are most relevant to the pathogenesis of OSA. Several studies have used ultrasound imaging to identify anatomic factors predisposing to OSA. However, most have investigated only anatomic mechanisms, which may explain the inconsistency in the observed results. Lateral pharyngeal wall thickness was identified as a major cause of OSA in an MRI study (Schwab et al. 1995). Compared with a measurement of lateral pharyngeal wall thickness by MRI, a measurement obtained by ultrasound is reliable and is also found to correlate with the severity of OSA (Liu et al. 2007). An earlier study found that the distance between lingual arteries, a surrogate measure of tongue base width, as acquired by Doppler mode ultrasound in submental coronal section, correlates with the occurrence and severity of OSA (Lahav et al. 2009). However, although maximal tongue height was measured, the authors failed to find a significant difference between control patients and OSA patients (Lahav et al. 2009). Another study (Ugur et al. 2011) used ultrasound to investigate the thickness of SFT in the neck and umbilicus in OSA patients and reported no significant correlation between polysomnographic findings and ultrasound measurements. SFT measured with ultrasound in our study also did not differ between OSA patients and controls. In a pilot study (Siegel et al. 2000), ultrasound examination of the pharynx was synchronized with PSG in five OSA patients during sleep and revealed that all apneic events identified by PSG were accompanied by an ultrasound event, which indicated preceding relaxation of the floor of mouth muscle before the onset of apnea, followed by posterior and inferior displacement of the tongue base toward the laryngopharynx during apnea. Notably, the characteristic feature of the ultrasound events was consistent for each subject and was observed in all samples. They concluded that ultrasound is a simple, dynamic and non-invasive clinical tool for visualizing the airway and has strong potential for use in diagnosis, treatment and prognosis of OSA.
Tongue base thickness in obstructive sleep apnea d J.-W. CHEN et al.
With the help of a miniature surface transducer, signal and image processing modules, image display and data storage units, monitoring of OSA patients’ retroglossal airways with ultrasound has the potential to be incorporated into polysomnography and to provide information about retroglossal airway behavior during natural sleep, which is very important in devising, applying and determining the effectiveness of tailor-made treatment modalities. Limitations of the study This study has several limitations. First, some of the control patients in this study had a higher than normal risk for OSA because they were recruited from a sleep clinic population. Morphologically, these control patients were more similar to OSA patients than to control patients selected from community populations. However, this suggests that this study likely underestimated the true differences. Second, the correlation between dynamic TBT measured by ultrasound and that measured by other more established imaging modalities (CT or MRI) was not tested because the patients had difficulty maintaining the MM during the prolonged scanning time of conventional CT or MRI. Further studies are needed specifically to validate the reliability of the dynamic ultrasound measuring technique by comparing it with ultrafast CT or cine MRI. Additionally, a pharyngeal pressure monitor was not used to record the effects of the MM. However, all patients were asked to practice the MM before examination, and three distinct measurements were used for the calculation to improve the reliability of this maneuver. Additional limitations of the ultrasound measuring technique include possible errors in subject alignment or probe position and arbitrary determination of the dimensions of the tongue base by the examiner. Although these issues may affect the accuracy of the technique, they can be minimized by a study design in which a standard procedure is used and in which a single operator performs all ultrasound examinations. Furthermore, this study did not investigate the reproducibility of ultrasound measurement. However, previous studies (Liu et al. 2007; Shu et al. 2013) confirmed that ultrasound measurements in the neck region had high intra-operator and interoperator reliability. Overall, the study populations had low ESS and BMI scores, which might indicate a milder form of the disease, and some patients were minimally symptomatic. However, this may have resulted from the lower obesity rate in Asian OSA patients compared with their Caucasian counterparts despite their similar prevalence rates of OSA. CONCLUSIONS Upper airway anatomy is fundamentally important in OSA pathogenesis. However, interacting effects of
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the abnormal neuromuscular control mechanism of the upper airway dilator muscle and other pathophysiologic factors such as respiratory arousal threshold and loop gain make OSA a multifactorial disease. Recent observations of tongue movement during quiet inspiration have revealed that OSA patients might have impaired respiratory control even when awake. This study developed a submental ultrasound technique for quantifying UA behavior in response to negative airway pressure while the subject is awake. Independent predictors of OSA included TBT measured by ultrasound with the MM and the difference between TBT with the MM and that without the MM. Submental ultrasound measurement of TBT with the MM is an alternative objective clinical modality for easy and tolerable evaluation of potential patterns and severity of airway obstruction in OSA patients while they are awake. Acknowledgments—The authors are grateful for technical support on this project provided by Chiu-Ping Wang and Shu-Hwei Fan. The authors also express their gratitude to all of the staff of the Center of Sleep Disorders and Division of Pulmonary Medicine of Cardinal Tien Hospital. Ted Knoy is appreciated for his editorial assistance. This research was supported by the National Science Council (NSC) of Taiwan (Project Grant NSC 102-2628-B-030-001-MY3).
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