pii: jc- 00060-15
http://dx.doi.org/10.5664/jcsm.5786
S CI E NT IF IC IN VES TIGATIONS
Lowest Oxyhemoglobin Saturation May Be an Independent Factor Influencing Auditory Function in Severe Obstructive Sleep Apnea Young Joon Seo, MD, PhD1,*; Sang Yoo Park, MD, PhD1,*; Hyo Jin Chung, MD2; Chang-Hoon Kim, MD, PhD2,3; Jeung-Gweon Lee, MD, PhD2; Sung Huhn Kim, MD, PhD2; Hyung-Ju Cho, MD, PhD2,3 Department of Otorhinolaryngology, Yonsei Wonju University College of Medicine, Seoul, South Korea; 2Department of Otolaryngology, Yonsei University College of Medicine Seoul, South Korea; 3The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea; *co-first authors 1
Study Objectives: The aims of this study were to determine if a correlation exists between the level of hypoxia induced by severe obstructive sleep apnea syndrome (OSAS) and the level of auditory dysfunction when verifying such a relationship using polysomnography (PSG). Methods: A retrospective review of 41 patients with severe OSAS was performed. Independent risk factors for hearing impairment included parameters of PSG, which were analyzed in two hearing groups at a level ≥ 40 decibels (dB). Results: Oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the hearing impairment group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). After adjusting for other risk factors, the sole variable that remained significant was lowest oxyhemoglobin saturation (total; p = 0.046). In the correlation analysis, a decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001). Conclusion: Our results indicated that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold. This finding could be predictive of possible hearing alternation in patients with severe OSAS. Commentary: A commentary on this article appears in this issue on page 641. Keywords: obstructive sleep apnea, sensorineural hearing loss, polysomnography, oxyhemoglobin saturation Citation: Seo YJ, Park SY, Chung HJ, Kim CH, Lee JG, Kim SH, Cho HJ. Lowest oxyhemoglobin saturation may be an independent factor influencing auditory function in severe obstructive sleep apnea. J Clin Sleep Med 2016;12(5):653–658.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: To verify our hypothesis that a correlation exists between the level of hypoxia induced by severe OSAS and the level of auditory dysfunction using polysomnography (PSG), We found that the sole variable that remained significant in parameters of PSG was lowest oxyhemoglobin saturation (total; p = 0.046). Oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the hearing impairment group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). Study Impact: With this study, we recommend that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold could be predictive of possible hearing alternation in patients with severe OSAS. Considering that severe OSAS might be a trigger for hearing loss, attention should be given to hearing evaluations in high-risk patients (e.g., obese middle-aged or elderly male) with OSAS screening.
Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder that occurs during sleep. It is characterized by episodic upper airway obstruction that interferes with normal respiratory gas exchange.1 OSAS causes hypoxia, a condition that has a comorbid relationship with cardiovascular and neurological system diseases.2–4 Chronic periodic hypoxia associated with OSAS can provoke oxidative stress and impaired vascular endothelial function, and it may also harm the vasa nervorum.5 The condition of chronic intermittent hypoxemia as seen in OSAS patients also potentially results in irreversible peripheral neuropathy.6 As the structures of the inner ear and the auditory nerve are highly dependent on a healthy oxygen supply, OSAS may interfere with the processes that generate and transmit nerve impulses within the auditory system.7 Research suggests that severe OSAS could represent a risk of dysfunction across the auditory pathway, particularly due to the resulting hypoxia.8 However, no correlation has been demonstrated between blood oxygen index (oxyhemoglobin saturation) and auditory dysfunction. The aim of this investigation was to verify our hypothesis that a correlation exists between the level of hypoxia induced by severe OSAS and the level of auditory dysfunction using polysomnography (PSG).
METHODS
Subjects
This retrospective study was performed on patients diagnosed with severe OSAS, as determined by overnight polysomnography (PSG) during the period from 2009 to 2013. The patients underwent an auditory test using pure tone audiometry (PTA) at our department of otorhinolaryngology within 3 months of 653
Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
YJ Seo, SY Park, HJ Chung et al. Auditory Dysfunction in Severe Obstructive Sleep Apnea
hypopnea + apnea) × 60 / total sleep time (in minutes); snoring index; number of respiration events (index) including numbers of apnea or hypopnea events; average heart rate (pulses/ min); duration below 90% oxyhemoglobin saturation (in min); lowest oxygen desaturation index; average oxyhemoglobin saturation (%); and lowest oxyhemoglobin saturation (%). We evaluated the possible correlations of these parameters with hearing level.
Figure 1—Mean hearing thresholds in pure tone audiometry between study groups.
Auditory Evaluation
Pure-tone thresholds were obtained for air conduction at 250 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, and 8,000 Hz. Audiologic data were reported in accordance with the methods recommended by the Hearing Committee of the American Academy of Otolaryngology Head and Neck Surgery.
Statistical Analysis
Statistical analysis was performed using the Statistical Package for Social Sciences Software (SPSS 18.0 for Windows, SPSS Inc., Chicago, IL, USA). Data are presented as mean and standard error of mean (SEM). The comparison of each variable between groups was performed using the Mann-Whitney U Test or the modified Rao-Scott χ2 test. To analyze the strength of the relationship between hearing levels and lowest oxyhemoglobin saturation, we conducted Pearson correlation analysis to determine linear associations between variables. Multivariable linear regression was used to assess associations between mean hearing thresholds and lowest oxyhemoglobin saturation (total), and the results were fitted with increasing degrees of adjustment. We adjusted for age (continuous), BMI (continuous), and sex (men or women). Models were further adjusted for the presence of hypertension (yes or no), diabetes (yes or no), dyslipidemia (yes or no), CKD (yes or no), smoking exposure (never or current), and alcohol intake (never or current). Multicollinearity was considered for predictor variables in the multiple linear model. Any characteristic that was significant at α < 0.20 in the univariate analysis with necessary related factors was entered into the multiple linear model. The final multivariable models for hearing and lowest oxyhemoglobin saturation included all variables identified by the selection procedures (backward, stepwise) that remained simultaneously significant at p < 0.05.
On analyzing the audiometry, the hearing impairment group showed higher thresholds than the Control group, statistically significant at every frequency on both ears (p < 0.05).
PSG as part of a regular health check-up (n = 10), based on a doctor’s recommendation (n = 11), or due to hearing disturbance (n = 20). Patients with a history that included effective drug treatments that were able to influence vascular reactivity and lung functions, hearing loss, or any middle-or innerear pathology were excluded. Patients with mild or moderate OSAS were also excluded, as several reports had already demonstrated a relation between hearing and severe OSAS. As determined by our criteria, 41 patients were included in the experiment. They were subsequently divided into two groups according to their hearing impairment: a “Control” group with no hearing impairment and an “HI” group with hearing impairment. For this experiment, hearing impairment was defined as a level ≥ 40 decibels (dB), measured through pure tone audiometry (PTA) and calculated using the following formula: (5,000 Hz + 2 × 1,000 Hz + 2,000 Hz) / 4.
R ES U LT S The HI group included 14 males and 5 females (Table 1). The mean age of the patients was 61.5 ± 3.3 years. The mean age of the Control group was 57.3 ± 1.6 years, and the ratio of males to females was about 3:1. No differences in body mass index (BMI), hypertension, cardiovascular disease, diabetes, or renal function were observed between the two groups. On analyzing the audiometry, the hearing impairment group showed higher thresholds than the Control group, statistically significant at every frequency on both ears (p < 0.05), as indicated in Figure 1. All OSAS patients had severe OSAS characterized by an AHI range > 30 (Control: 39.9 ± 4.9; HI: 39.6 ± 6.3; p = 0.491; Table 2). The sleep time at each stage was not significantly
Sleep Studies
All patients underwent overnight PSG performed by study-certified technicians using a standardized protocol and following the guidelines of the American Academy of Sleep Medicine (AASM). According to these guidelines, as well as the apnea-hypopnea index (AHI), (apnea + hypopnea per hour of sleep) > 30 suggests severe OSAS. We considered the parameters of PSG through a variety of indices and measurements: sleep time (total, stage N1, stage N2, stage N3, and stage R minutes); apnea-hypopnea index (AHI); respiratory disturbance index (RDI), defined as ([respiratory effort-related arousals] + Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
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Table 1—Baseline characteristics of the study and control groups. Characteristic Age (years) Gender, male / female Height (centimeters) Weight (kg) BMI (kg/m2) Tinnitus HTN DM Dyslipidemia CKD Smoking Alcohol Mean hearing thresholds (dB) right left ESS MSQ (total)
No Hearing Impairment (n = 22) 57.3 ± 1.6 17 (77.3) / 5 (22.7) 169.9 ± 1.5 76.1 ± 3.2 26.3 ± 0.9 1 (4.6) 5 (22.7) 5 (22.7) 5 (22.7) 2 (9.1) 8 (36.4) 4 (18.2)
Hearing Impairment (n = 19) 61.5 ± 3.3 14 (73.7) / 5 (26.3) 164.3 ± 2.7 69.8 ± 2.9 25.9 ± 0.9 12 (63) 4 (21.1) 5 (26.3) 4 (21.1) 2 (10.5) 9 (47.4) 4 (21.1)
p value 0.047* 0.059 0.151 0.312 0.766 < 0.001* 0.624 0.664 0.784 0.874 0.522 0.706
17.0 ± 2.1 19.8 ± 3.4 7.7 ± 1.2 16.2 ± 2.7
45.3 ± 4.5 39.4 ± 3.8 9.5 ± 1.5 16.8 ± 3.6
< 0.001* < 0.001* 0.352 0.721
Values are expressed as mean ± standard error of mean or number (percentage). *p value < 0.05. BMI, body mass index; HTN, hypertension; DM, diabetes mellitus; CKD, chronic kidney disease; dB, decibel; ESS, Epworth sleepiness scale; MSQ, mini sleep questionnaire items.
Table 2—Polysomnography data of the study and control groups. Parameters Total sleep time (min) Total stage N1 (min) Total stage N2(min) Total stage N3 (min) Total stage R (min) A/H index RDI Snoring index Sat < 90% duration (min)
No Hearing Impairment (n = 22) 354.0 ± 6.7 23.2 ± 2.2 55.5 ± 2.6 3.2 ± 1.3 18.1 ± 1.4 39.9 ± 4.9 46.1 ± 3.9 87.6 ± 4.2 12.1 ± 3.7
Hearing Impairment (n = 19) 342.8 ± 5.4 33.9 ± 5.0 42.5 ± 5.1 3.6 ± 1.6 19.9 ± 2.2 39.6 ± 6.3 64.6 ± 5.4 120.3 ± 4.1 13.2 ± 3.2
p value 0.625 0.064 0.061 0.830 0.491 0.491 0.234 0.263 0.192
Number of respiration events Apnea (NREM) A/H (NREM) Apnea (R) A/H (R)
10.4 ± 3.5 38.8 ± 4.9 12.4 ± 3.5 37.2 ± 5.1
18.8 ± 5.0 37.5 ± 6.7 20.5 ± 4.6 37.5 ± 5.9
0.179 0.307 0.171 0.191
Average of heart rate
63.4 ± 2.0
62.7 ± 3.5
0.892
Oxygen desaturation index NREM REM Total
37.4 ± 1.1 46.6 ± 2.1 33.4 ± 1.1
30.7 ± 1.0 17.1 ± 0.9 24.8 ± 0.8
0.746 0.235 0.607
Average oxyhemoglobin saturation(%) NREM REM Total
93.1 ± 1.5 92.2 ± 2.1 92.7 ± 4.3
93.0 ± 0.8 92.1 ± 0.7 92.6 ± 0.8
0.976 0.728 0.871
Lowest oxyhemoglobin saturation(%) NREM REM Total
86.6 ± 2.0 85.3 ± 2.2 86.1 ± 1.0
62.9 ± 9.9 75.3 ± 3.5 71.7 ± 4.6
0.039* 0.029* 0.001*
Values are expressed as mean ± standard error of mean or number (percentage). *p value < 0.05. RDI, respiratory disturbance index; NREM, non-rapid eye movement stage; R, rapid eye movement stage; A/H, apnea and hypopnea.
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Table 3—Effects of lowest oxyhemoglobin saturation on auditory function, after adjusting for age, sex, BMI, and other risk factors. Outcome Lowest oxyhemoglobin saturation (total) Age Gender BMI HTN DM Dyslipidemia CKD Smoking Alcohol
β Coefficient (SE) −0.361 (0.370) 0.096 (0.302) 0.054 (7.238) 0.626 (0.184) 0.648 (9.005) 0.263 (8.434) 0.266 (12.925) 0.074 (10.440) 0.258 (9.844) 0.445 (8.028)
p value 0.046* 0.581 0.735 0.559 0.037* 0.205 0.182 0.711 0.350 0.081
*p value < 0.05. BMI, body mass index; HTN, hypertension; DM, diabetes mellitus; CKD, chronic kidney disease.
Figure 2—Graphs of correlation analyses for lowest oxyhemoglobin saturation and mean hearing threshold on both ears.
remained significant in parameters of PSG was lowest oxyhemoglobin saturation (total; p = 0.046). The R-squared output of this model, which measured the proportion of the variance of hearing by variables, was 0.892. The β coefficient between the hearing and lowest oxyhemoglobin saturation (total) was –0.361, a negative correlation. There were fewer than 4 variance inflation factors for all variables in the model. In the correlation analysis, Figure 2 shows decreasing lowest oxyhemoglobin saturation (for all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears). D I SCUS S I O N Several studies have revealed auditory dysfunction in patients affected by severe OSAS in the absence of other auditory risk factors. This suggests that hypoxia brought on by OSAS could represent a risk to the auditory pathway.8–10 A study by Fischer et al.11 suggested that sudden deafness may also be an indicator of damage secondary to such risk factors as hypertension, diabetes, and hyperlipidemia, which were highly significant for OSAS patients. Although the effects of chronic intermittent hypoxia during sleep result in alterations to the normal physiology of several organ systems in the body,2–4 only a small amount of research has been performed to explore the effect of OSAS and its resulting hypoxia on the fragile auditory system. Therefore, we attempted to study the consequence of OSAS on the hearing of severe OSAS patients, excluding those already known to have hearing loss and non-OSAS subjects without hearing loss. However, it is also important to further evaluate various factors potentially related to preserved or worsened hearing in severe OSAS. Such results could be predictive of possible hearing alternation in patients with severe OSAS. After adjustment for risk factors such as sex, age, BMI, HTN, DM, dyslipidemia, and CKD using the multiple linear regression model, we found that lowest oxyhemoglobin saturation was the only variable to affect the hearing threshold (p = 0.046 during total sleep stage). Furthermore, there was a negative linear correlation between the mean hearing threshold (p < 0.001) and lowest oxyhemoglobin saturation (total).
A decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears).
different across groups. Statistical analysis showed no significant differences in the most important factors of the polysomnography, including RDI, snoring index, duration of < 90% oxyhemoglobin saturation, number of respiration events during each sleep stage, and heart rate between the groups. However, oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the HI group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). In the multivariate analysis modeling of hearing and lowest oxyhemoglobin saturation (Table 3), the sole variable that Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
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Chronic intermittent hypoxemia is one of the major symptoms of OSAS, and the level of lowest oxyhemoglobin saturation correlates with OSAS severity.12,13 A recent, large, cross-sectional study of healthy, middle-aged and older adults found a direct, dose-dependent correlation between sleep time below 90% oxyhemoglobin saturation and the odds of systemic disease.14 Dziewas et al. showed that recurrent intermittent hypoxemia may be considered a risk factor for peripheral sensory nerve dysfunction and suggested that treatment for OSAS might result in improved function of these nerves.15 A low level of oxygen perfusion may act alone or in concert with other ailments to negatively influence the neuronal or vascular function of the auditory pathway. In Figure 2, decreasing lowest oxyhemoglobin saturation corresponds with a higher hearing threshold. Hearing at higher frequencies has larger gaps between the two groups. This finding is consistent with the theory that a higher susceptibility of hair cells in the basal turn to the damage caused by free radicals.16–19 We were unable to analyze the exact relation to hearing according to graded groups of lowest oxyhemoglobin saturation (below 90%, 85%, or 75%), as the groups contained too few patients. However, our results demonstrated a relation between hearing and lowest oxyhemoglobin saturation in the correlation graphs. A decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears). Our study was limited due to the small sample size. As such, it was difficult to rule out the effects of the multiple variables, even with a multiple linear regression test. However, the sample groups did exhibit similarities in this set of variables, and no correlation was found to hearing loss within the set. We were unable to consider the risk factors for snoring noise level and their effects on decreased hearing, as we did not check for noise in this retrospective study. We intend to proceed with a randomized case-controlled study that tests the hearing of patients who are diagnosed for OSAS and have PSG test results, which may clarify whether the auditory system can be altered by OSAS. This further research may ultimately suggest that effective treatment of OSAS may also improve auditory function. In conclusion, this result that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold could be predictive of possible hearing alternation in patients with severe OSAS. Considering that severe OSAS might be a trigger for hearing loss, attention should be given to hearing evaluations in high-risk patients (e.g., obese middleaged or elderly male) with OSAS screening.
HI group, hearing impairment group MSQ, mini sleep questionnaire items OSAS, obstructive sleep apnea syndrome PTA, pure tone audiometry PSG, polysomnography RDI, respiratory disturbance index REM, rapid eye movement SEM, standard error of mean R E FE R E N CES 1. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 1996;153:866–78. 2. Fletcher EC. The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. Am J Med 1995;98:118–28 3. Hui DS, Wong TY, Ko FW, et al. Prevalence of sleep disturbances in Chinese patients with end-stage renal failure on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 2000;36:783–8 4. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences and presentations. Circulation 1998;97:2154–9. 5. Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more. Am J Respir Crit Care Med 2008;177:369–75 6. Fanfulla F, Grassi M, Taurino AE, Lupo ND, Trentin R. The relationship of daytime hypoxemia and nocturnal hypoxia in obstructive sleep apnea syndrome. Sleep 2008;31:249–55 7. Gupta PP, Sood S, Atreja A, Agarwal D. Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease. Ann Thorac Med 2008;3:128–34 8. Casale M, Vesperini E, Potena M, et al. Is obstructive sleep apnea syndrome a risk factor for auditory pathway? Sleep Breath 2012;16:413–7 9. Carlile S, Paterson DJ. The effects of chronic hypoxia on human auditory system sensitivity. Aviat Space Environ Med 1992;63:1093–7 10. Mazurek B, Haupt H, Georgiewa P, Klapp BF, Reisshauer A. A model of peripherally developing hearing loss and tinnitus based on the role of hypoxia and ischemia. Med Hypotheses 2006;67:892–9 11. Fischer Y, Yakinthou A, Mann WJ. Prevalence of obstructive sleep apnea syndrome (OSA) in patients with sudden hearing loss. A pilot study. HNO 2003;51:462–6 12. Weiss JW, Remsburg S, Garpestad E, et al. Hemodynamic consequences of obstructive sleep apnea. Sleep 1996;19:388–97 13. Min HJ, Park AH, Kim DH, Cho HJ. Neck circumference and lowest oxygen saturation are independently associated with high coexistence of hypertension in obstructive sleep apnea. Yonsei Med J 2014;55:1310–7 14. Nieto F, Young T, Lind BK, et al. Association of sleep- disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829–36 15. Pfeifer G, Kunze K, Bruch M, Kutzner M, Ladurner G, Malin JP. Polyneuropathy associated with chronic hypoxaemia: prevalence in patients with chronic obstructive pulmonary disease. J Neurol 1990;237:230–3 16. Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001;155:1–8 17. Chang MY, Choi BY. Strategy for the customized mass screening of genetic sensorineural hearing loss in koreans. Korean J Audiol 2014;18:45–9. 18. Rastegarianzadeh N, Shahbodaghi M, Faghihzadeh S. Study of phonological awareness of preschool and school aged children with cochlear implant and normal hearing. Korean J Audiol 2014;18:50–3. 19. Mukari SZ, Wahat NH, Mazlan R. Effects of ageing and hearing thresholds on speech perception in quiet and in noise perceived in different locations. Korean J Audiol 2014;18:112–8.
A B B R E V I AT I O N S AASM, American Academy of Sleep Medicine AHI, apnea-hypopnea index BMI, body mass index CKD, chronic kidney diseas dB, decibel ESS, Epworth sleepiness scale
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SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N
D I SCLO S U R E S TAT E M E N T
Submitted for publication February, 2015 Submitted in final revised form November, 2015 Accepted for publication December, 2015 Address correspondence to: Hyung-Ju Cho, MD, PhD; Sung Huhn Kim, MD, PhD Department of Otorhinolaryngology, Yonsei University College of Medicine 250 Seongsanno, 134 Shinchon-dong, Seodaemun-gu, 120-752, Seoul, South Korea; Tel: +82-10-8652-2055; Fax: +82-2-2228-3603; Email: [email protected] and [email protected]
Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
This was not an industry supported study. This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science, ICT & Future Planning (2013M3A9D5072551) to C.H. Kim. This research was supported (in part) by the Yonsei University Future-leading Research Initiative of 2014 (2014-22-0131) to C.H. Kim. This research was supported (in part) by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (NRF2013R1A1A1010151) to H. J. Cho. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have indicated no financial conflicts of interest.
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http://dx.doi.org/10.5664/jcsm.5786
S CI E NT IF IC IN VES TIGATIONS
Lowest Oxyhemoglobin Saturation May Be an Independent Factor Influencing Auditory Function in Severe Obstructive Sleep Apnea Young Joon Seo, MD, PhD1,*; Sang Yoo Park, MD, PhD1,*; Hyo Jin Chung, MD2; Chang-Hoon Kim, MD, PhD2,3; Jeung-Gweon Lee, MD, PhD2; Sung Huhn Kim, MD, PhD2; Hyung-Ju Cho, MD, PhD2,3 Department of Otorhinolaryngology, Yonsei Wonju University College of Medicine, Seoul, South Korea; 2Department of Otolaryngology, Yonsei University College of Medicine Seoul, South Korea; 3The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea; *co-first authors 1
Study Objectives: The aims of this study were to determine if a correlation exists between the level of hypoxia induced by severe obstructive sleep apnea syndrome (OSAS) and the level of auditory dysfunction when verifying such a relationship using polysomnography (PSG). Methods: A retrospective review of 41 patients with severe OSAS was performed. Independent risk factors for hearing impairment included parameters of PSG, which were analyzed in two hearing groups at a level ≥ 40 decibels (dB). Results: Oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the hearing impairment group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). After adjusting for other risk factors, the sole variable that remained significant was lowest oxyhemoglobin saturation (total; p = 0.046). In the correlation analysis, a decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001). Conclusion: Our results indicated that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold. This finding could be predictive of possible hearing alternation in patients with severe OSAS. Commentary: A commentary on this article appears in this issue on page 641. Keywords: obstructive sleep apnea, sensorineural hearing loss, polysomnography, oxyhemoglobin saturation Citation: Seo YJ, Park SY, Chung HJ, Kim CH, Lee JG, Kim SH, Cho HJ. Lowest oxyhemoglobin saturation may be an independent factor influencing auditory function in severe obstructive sleep apnea. J Clin Sleep Med 2016;12(5):653–658.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: To verify our hypothesis that a correlation exists between the level of hypoxia induced by severe OSAS and the level of auditory dysfunction using polysomnography (PSG), We found that the sole variable that remained significant in parameters of PSG was lowest oxyhemoglobin saturation (total; p = 0.046). Oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the hearing impairment group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). Study Impact: With this study, we recommend that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold could be predictive of possible hearing alternation in patients with severe OSAS. Considering that severe OSAS might be a trigger for hearing loss, attention should be given to hearing evaluations in high-risk patients (e.g., obese middle-aged or elderly male) with OSAS screening.
Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder that occurs during sleep. It is characterized by episodic upper airway obstruction that interferes with normal respiratory gas exchange.1 OSAS causes hypoxia, a condition that has a comorbid relationship with cardiovascular and neurological system diseases.2–4 Chronic periodic hypoxia associated with OSAS can provoke oxidative stress and impaired vascular endothelial function, and it may also harm the vasa nervorum.5 The condition of chronic intermittent hypoxemia as seen in OSAS patients also potentially results in irreversible peripheral neuropathy.6 As the structures of the inner ear and the auditory nerve are highly dependent on a healthy oxygen supply, OSAS may interfere with the processes that generate and transmit nerve impulses within the auditory system.7 Research suggests that severe OSAS could represent a risk of dysfunction across the auditory pathway, particularly due to the resulting hypoxia.8 However, no correlation has been demonstrated between blood oxygen index (oxyhemoglobin saturation) and auditory dysfunction. The aim of this investigation was to verify our hypothesis that a correlation exists between the level of hypoxia induced by severe OSAS and the level of auditory dysfunction using polysomnography (PSG).
METHODS
Subjects
This retrospective study was performed on patients diagnosed with severe OSAS, as determined by overnight polysomnography (PSG) during the period from 2009 to 2013. The patients underwent an auditory test using pure tone audiometry (PTA) at our department of otorhinolaryngology within 3 months of 653
Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
YJ Seo, SY Park, HJ Chung et al. Auditory Dysfunction in Severe Obstructive Sleep Apnea
hypopnea + apnea) × 60 / total sleep time (in minutes); snoring index; number of respiration events (index) including numbers of apnea or hypopnea events; average heart rate (pulses/ min); duration below 90% oxyhemoglobin saturation (in min); lowest oxygen desaturation index; average oxyhemoglobin saturation (%); and lowest oxyhemoglobin saturation (%). We evaluated the possible correlations of these parameters with hearing level.
Figure 1—Mean hearing thresholds in pure tone audiometry between study groups.
Auditory Evaluation
Pure-tone thresholds were obtained for air conduction at 250 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, and 8,000 Hz. Audiologic data were reported in accordance with the methods recommended by the Hearing Committee of the American Academy of Otolaryngology Head and Neck Surgery.
Statistical Analysis
Statistical analysis was performed using the Statistical Package for Social Sciences Software (SPSS 18.0 for Windows, SPSS Inc., Chicago, IL, USA). Data are presented as mean and standard error of mean (SEM). The comparison of each variable between groups was performed using the Mann-Whitney U Test or the modified Rao-Scott χ2 test. To analyze the strength of the relationship between hearing levels and lowest oxyhemoglobin saturation, we conducted Pearson correlation analysis to determine linear associations between variables. Multivariable linear regression was used to assess associations between mean hearing thresholds and lowest oxyhemoglobin saturation (total), and the results were fitted with increasing degrees of adjustment. We adjusted for age (continuous), BMI (continuous), and sex (men or women). Models were further adjusted for the presence of hypertension (yes or no), diabetes (yes or no), dyslipidemia (yes or no), CKD (yes or no), smoking exposure (never or current), and alcohol intake (never or current). Multicollinearity was considered for predictor variables in the multiple linear model. Any characteristic that was significant at α < 0.20 in the univariate analysis with necessary related factors was entered into the multiple linear model. The final multivariable models for hearing and lowest oxyhemoglobin saturation included all variables identified by the selection procedures (backward, stepwise) that remained simultaneously significant at p < 0.05.
On analyzing the audiometry, the hearing impairment group showed higher thresholds than the Control group, statistically significant at every frequency on both ears (p < 0.05).
PSG as part of a regular health check-up (n = 10), based on a doctor’s recommendation (n = 11), or due to hearing disturbance (n = 20). Patients with a history that included effective drug treatments that were able to influence vascular reactivity and lung functions, hearing loss, or any middle-or innerear pathology were excluded. Patients with mild or moderate OSAS were also excluded, as several reports had already demonstrated a relation between hearing and severe OSAS. As determined by our criteria, 41 patients were included in the experiment. They were subsequently divided into two groups according to their hearing impairment: a “Control” group with no hearing impairment and an “HI” group with hearing impairment. For this experiment, hearing impairment was defined as a level ≥ 40 decibels (dB), measured through pure tone audiometry (PTA) and calculated using the following formula: (5,000 Hz + 2 × 1,000 Hz + 2,000 Hz) / 4.
R ES U LT S The HI group included 14 males and 5 females (Table 1). The mean age of the patients was 61.5 ± 3.3 years. The mean age of the Control group was 57.3 ± 1.6 years, and the ratio of males to females was about 3:1. No differences in body mass index (BMI), hypertension, cardiovascular disease, diabetes, or renal function were observed between the two groups. On analyzing the audiometry, the hearing impairment group showed higher thresholds than the Control group, statistically significant at every frequency on both ears (p < 0.05), as indicated in Figure 1. All OSAS patients had severe OSAS characterized by an AHI range > 30 (Control: 39.9 ± 4.9; HI: 39.6 ± 6.3; p = 0.491; Table 2). The sleep time at each stage was not significantly
Sleep Studies
All patients underwent overnight PSG performed by study-certified technicians using a standardized protocol and following the guidelines of the American Academy of Sleep Medicine (AASM). According to these guidelines, as well as the apnea-hypopnea index (AHI), (apnea + hypopnea per hour of sleep) > 30 suggests severe OSAS. We considered the parameters of PSG through a variety of indices and measurements: sleep time (total, stage N1, stage N2, stage N3, and stage R minutes); apnea-hypopnea index (AHI); respiratory disturbance index (RDI), defined as ([respiratory effort-related arousals] + Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
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Table 1—Baseline characteristics of the study and control groups. Characteristic Age (years) Gender, male / female Height (centimeters) Weight (kg) BMI (kg/m2) Tinnitus HTN DM Dyslipidemia CKD Smoking Alcohol Mean hearing thresholds (dB) right left ESS MSQ (total)
No Hearing Impairment (n = 22) 57.3 ± 1.6 17 (77.3) / 5 (22.7) 169.9 ± 1.5 76.1 ± 3.2 26.3 ± 0.9 1 (4.6) 5 (22.7) 5 (22.7) 5 (22.7) 2 (9.1) 8 (36.4) 4 (18.2)
Hearing Impairment (n = 19) 61.5 ± 3.3 14 (73.7) / 5 (26.3) 164.3 ± 2.7 69.8 ± 2.9 25.9 ± 0.9 12 (63) 4 (21.1) 5 (26.3) 4 (21.1) 2 (10.5) 9 (47.4) 4 (21.1)
p value 0.047* 0.059 0.151 0.312 0.766 < 0.001* 0.624 0.664 0.784 0.874 0.522 0.706
17.0 ± 2.1 19.8 ± 3.4 7.7 ± 1.2 16.2 ± 2.7
45.3 ± 4.5 39.4 ± 3.8 9.5 ± 1.5 16.8 ± 3.6
< 0.001* < 0.001* 0.352 0.721
Values are expressed as mean ± standard error of mean or number (percentage). *p value < 0.05. BMI, body mass index; HTN, hypertension; DM, diabetes mellitus; CKD, chronic kidney disease; dB, decibel; ESS, Epworth sleepiness scale; MSQ, mini sleep questionnaire items.
Table 2—Polysomnography data of the study and control groups. Parameters Total sleep time (min) Total stage N1 (min) Total stage N2(min) Total stage N3 (min) Total stage R (min) A/H index RDI Snoring index Sat < 90% duration (min)
No Hearing Impairment (n = 22) 354.0 ± 6.7 23.2 ± 2.2 55.5 ± 2.6 3.2 ± 1.3 18.1 ± 1.4 39.9 ± 4.9 46.1 ± 3.9 87.6 ± 4.2 12.1 ± 3.7
Hearing Impairment (n = 19) 342.8 ± 5.4 33.9 ± 5.0 42.5 ± 5.1 3.6 ± 1.6 19.9 ± 2.2 39.6 ± 6.3 64.6 ± 5.4 120.3 ± 4.1 13.2 ± 3.2
p value 0.625 0.064 0.061 0.830 0.491 0.491 0.234 0.263 0.192
Number of respiration events Apnea (NREM) A/H (NREM) Apnea (R) A/H (R)
10.4 ± 3.5 38.8 ± 4.9 12.4 ± 3.5 37.2 ± 5.1
18.8 ± 5.0 37.5 ± 6.7 20.5 ± 4.6 37.5 ± 5.9
0.179 0.307 0.171 0.191
Average of heart rate
63.4 ± 2.0
62.7 ± 3.5
0.892
Oxygen desaturation index NREM REM Total
37.4 ± 1.1 46.6 ± 2.1 33.4 ± 1.1
30.7 ± 1.0 17.1 ± 0.9 24.8 ± 0.8
0.746 0.235 0.607
Average oxyhemoglobin saturation(%) NREM REM Total
93.1 ± 1.5 92.2 ± 2.1 92.7 ± 4.3
93.0 ± 0.8 92.1 ± 0.7 92.6 ± 0.8
0.976 0.728 0.871
Lowest oxyhemoglobin saturation(%) NREM REM Total
86.6 ± 2.0 85.3 ± 2.2 86.1 ± 1.0
62.9 ± 9.9 75.3 ± 3.5 71.7 ± 4.6
0.039* 0.029* 0.001*
Values are expressed as mean ± standard error of mean or number (percentage). *p value < 0.05. RDI, respiratory disturbance index; NREM, non-rapid eye movement stage; R, rapid eye movement stage; A/H, apnea and hypopnea.
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Table 3—Effects of lowest oxyhemoglobin saturation on auditory function, after adjusting for age, sex, BMI, and other risk factors. Outcome Lowest oxyhemoglobin saturation (total) Age Gender BMI HTN DM Dyslipidemia CKD Smoking Alcohol
β Coefficient (SE) −0.361 (0.370) 0.096 (0.302) 0.054 (7.238) 0.626 (0.184) 0.648 (9.005) 0.263 (8.434) 0.266 (12.925) 0.074 (10.440) 0.258 (9.844) 0.445 (8.028)
p value 0.046* 0.581 0.735 0.559 0.037* 0.205 0.182 0.711 0.350 0.081
*p value < 0.05. BMI, body mass index; HTN, hypertension; DM, diabetes mellitus; CKD, chronic kidney disease.
Figure 2—Graphs of correlation analyses for lowest oxyhemoglobin saturation and mean hearing threshold on both ears.
remained significant in parameters of PSG was lowest oxyhemoglobin saturation (total; p = 0.046). The R-squared output of this model, which measured the proportion of the variance of hearing by variables, was 0.892. The β coefficient between the hearing and lowest oxyhemoglobin saturation (total) was –0.361, a negative correlation. There were fewer than 4 variance inflation factors for all variables in the model. In the correlation analysis, Figure 2 shows decreasing lowest oxyhemoglobin saturation (for all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears). D I SCUS S I O N Several studies have revealed auditory dysfunction in patients affected by severe OSAS in the absence of other auditory risk factors. This suggests that hypoxia brought on by OSAS could represent a risk to the auditory pathway.8–10 A study by Fischer et al.11 suggested that sudden deafness may also be an indicator of damage secondary to such risk factors as hypertension, diabetes, and hyperlipidemia, which were highly significant for OSAS patients. Although the effects of chronic intermittent hypoxia during sleep result in alterations to the normal physiology of several organ systems in the body,2–4 only a small amount of research has been performed to explore the effect of OSAS and its resulting hypoxia on the fragile auditory system. Therefore, we attempted to study the consequence of OSAS on the hearing of severe OSAS patients, excluding those already known to have hearing loss and non-OSAS subjects without hearing loss. However, it is also important to further evaluate various factors potentially related to preserved or worsened hearing in severe OSAS. Such results could be predictive of possible hearing alternation in patients with severe OSAS. After adjustment for risk factors such as sex, age, BMI, HTN, DM, dyslipidemia, and CKD using the multiple linear regression model, we found that lowest oxyhemoglobin saturation was the only variable to affect the hearing threshold (p = 0.046 during total sleep stage). Furthermore, there was a negative linear correlation between the mean hearing threshold (p < 0.001) and lowest oxyhemoglobin saturation (total).
A decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears).
different across groups. Statistical analysis showed no significant differences in the most important factors of the polysomnography, including RDI, snoring index, duration of < 90% oxyhemoglobin saturation, number of respiration events during each sleep stage, and heart rate between the groups. However, oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the HI group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). In the multivariate analysis modeling of hearing and lowest oxyhemoglobin saturation (Table 3), the sole variable that Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
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Chronic intermittent hypoxemia is one of the major symptoms of OSAS, and the level of lowest oxyhemoglobin saturation correlates with OSAS severity.12,13 A recent, large, cross-sectional study of healthy, middle-aged and older adults found a direct, dose-dependent correlation between sleep time below 90% oxyhemoglobin saturation and the odds of systemic disease.14 Dziewas et al. showed that recurrent intermittent hypoxemia may be considered a risk factor for peripheral sensory nerve dysfunction and suggested that treatment for OSAS might result in improved function of these nerves.15 A low level of oxygen perfusion may act alone or in concert with other ailments to negatively influence the neuronal or vascular function of the auditory pathway. In Figure 2, decreasing lowest oxyhemoglobin saturation corresponds with a higher hearing threshold. Hearing at higher frequencies has larger gaps between the two groups. This finding is consistent with the theory that a higher susceptibility of hair cells in the basal turn to the damage caused by free radicals.16–19 We were unable to analyze the exact relation to hearing according to graded groups of lowest oxyhemoglobin saturation (below 90%, 85%, or 75%), as the groups contained too few patients. However, our results demonstrated a relation between hearing and lowest oxyhemoglobin saturation in the correlation graphs. A decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R 2 = 0.297; p < 0.001; both ears). Our study was limited due to the small sample size. As such, it was difficult to rule out the effects of the multiple variables, even with a multiple linear regression test. However, the sample groups did exhibit similarities in this set of variables, and no correlation was found to hearing loss within the set. We were unable to consider the risk factors for snoring noise level and their effects on decreased hearing, as we did not check for noise in this retrospective study. We intend to proceed with a randomized case-controlled study that tests the hearing of patients who are diagnosed for OSAS and have PSG test results, which may clarify whether the auditory system can be altered by OSAS. This further research may ultimately suggest that effective treatment of OSAS may also improve auditory function. In conclusion, this result that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold could be predictive of possible hearing alternation in patients with severe OSAS. Considering that severe OSAS might be a trigger for hearing loss, attention should be given to hearing evaluations in high-risk patients (e.g., obese middleaged or elderly male) with OSAS screening.
HI group, hearing impairment group MSQ, mini sleep questionnaire items OSAS, obstructive sleep apnea syndrome PTA, pure tone audiometry PSG, polysomnography RDI, respiratory disturbance index REM, rapid eye movement SEM, standard error of mean R E FE R E N CES 1. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 1996;153:866–78. 2. Fletcher EC. The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. Am J Med 1995;98:118–28 3. Hui DS, Wong TY, Ko FW, et al. Prevalence of sleep disturbances in Chinese patients with end-stage renal failure on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 2000;36:783–8 4. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences and presentations. Circulation 1998;97:2154–9. 5. Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more. Am J Respir Crit Care Med 2008;177:369–75 6. Fanfulla F, Grassi M, Taurino AE, Lupo ND, Trentin R. The relationship of daytime hypoxemia and nocturnal hypoxia in obstructive sleep apnea syndrome. Sleep 2008;31:249–55 7. Gupta PP, Sood S, Atreja A, Agarwal D. Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease. Ann Thorac Med 2008;3:128–34 8. Casale M, Vesperini E, Potena M, et al. Is obstructive sleep apnea syndrome a risk factor for auditory pathway? Sleep Breath 2012;16:413–7 9. Carlile S, Paterson DJ. The effects of chronic hypoxia on human auditory system sensitivity. Aviat Space Environ Med 1992;63:1093–7 10. Mazurek B, Haupt H, Georgiewa P, Klapp BF, Reisshauer A. A model of peripherally developing hearing loss and tinnitus based on the role of hypoxia and ischemia. Med Hypotheses 2006;67:892–9 11. Fischer Y, Yakinthou A, Mann WJ. Prevalence of obstructive sleep apnea syndrome (OSA) in patients with sudden hearing loss. A pilot study. HNO 2003;51:462–6 12. Weiss JW, Remsburg S, Garpestad E, et al. Hemodynamic consequences of obstructive sleep apnea. Sleep 1996;19:388–97 13. Min HJ, Park AH, Kim DH, Cho HJ. Neck circumference and lowest oxygen saturation are independently associated with high coexistence of hypertension in obstructive sleep apnea. Yonsei Med J 2014;55:1310–7 14. Nieto F, Young T, Lind BK, et al. Association of sleep- disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829–36 15. Pfeifer G, Kunze K, Bruch M, Kutzner M, Ladurner G, Malin JP. Polyneuropathy associated with chronic hypoxaemia: prevalence in patients with chronic obstructive pulmonary disease. J Neurol 1990;237:230–3 16. Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001;155:1–8 17. Chang MY, Choi BY. Strategy for the customized mass screening of genetic sensorineural hearing loss in koreans. Korean J Audiol 2014;18:45–9. 18. Rastegarianzadeh N, Shahbodaghi M, Faghihzadeh S. Study of phonological awareness of preschool and school aged children with cochlear implant and normal hearing. Korean J Audiol 2014;18:50–3. 19. Mukari SZ, Wahat NH, Mazlan R. Effects of ageing and hearing thresholds on speech perception in quiet and in noise perceived in different locations. Korean J Audiol 2014;18:112–8.
A B B R E V I AT I O N S AASM, American Academy of Sleep Medicine AHI, apnea-hypopnea index BMI, body mass index CKD, chronic kidney diseas dB, decibel ESS, Epworth sleepiness scale
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SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N
D I SCLO S U R E S TAT E M E N T
Submitted for publication February, 2015 Submitted in final revised form November, 2015 Accepted for publication December, 2015 Address correspondence to: Hyung-Ju Cho, MD, PhD; Sung Huhn Kim, MD, PhD Department of Otorhinolaryngology, Yonsei University College of Medicine 250 Seongsanno, 134 Shinchon-dong, Seodaemun-gu, 120-752, Seoul, South Korea; Tel: +82-10-8652-2055; Fax: +82-2-2228-3603; Email: [email protected] and [email protected]
Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016
This was not an industry supported study. This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science, ICT & Future Planning (2013M3A9D5072551) to C.H. Kim. This research was supported (in part) by the Yonsei University Future-leading Research Initiative of 2014 (2014-22-0131) to C.H. Kim. This research was supported (in part) by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (NRF2013R1A1A1010151) to H. J. Cho. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have indicated no financial conflicts of interest.
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