Factors Influencing Sleep Time With Oxygen Saturation Below 90% in Sleep-Disordered Breathing

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Factors Influencing Sleep Time With Oxygen Saturation Below 90% in Sleep-Disordered Breathing Asli Bostanci, MD; Murat Turhan, MD; Selen Bozkurt, MSc Objectives/Hypothesis: To determine factors influencing sleep time with oxygen saturation below 90% (ST 90 ) in a population referred to a tertiary sleep center for assessment of possible sleep-disordered breathing (SDB). Study Design: Retrospective review of demographic and polysomnographic data of 731 consecutive patients with suspected SDB. Methods: Bivariate correlation analyses were performed, and Spearman rho coefficients were calculated. Variables with a marginal association with ST 90 (P <.05) in the bivariate analysis were included into the multiple regression analysis. Results: The distributions of SDB were as follows: normal/simple snoring, 18.2%; mild obstructive sleep apnea (OSA), 25.6%; moderate OSA, 17.4%; and severe OSA, 38.9%. The univariate analysis revealed a significant correlation between ST 90 and age (r ), body mass index (BMI) (r ), arousal index (r ), apnea-hypopnea index (AHI) (r ), mean oxygen saturation (SaO 2 )(r ), and mean O 2 desaturation (r ) (P <.001 for all parameters). In multiple regression analysis, age (P <.001), BMI (P 5.040), male gender (P 5.001), AHI (P <.001), mean SaO 2 (P <.001), and mean O 2 desaturation (P <.001) were found to be independent parameters influencing ST 90. Furthermore, these parameters explained a significant proportion of variance in ST 90 (R , F (6, 729) , P <.001). Although there was a strong correlation between AHI and ST 90 (r , P <.001), a large variation of ST 90 values was observed, especially within the severe OSA group. Conclusions: The study results provide supporting evidence that patients with similar AHI may have quite different values of ST 90, and thereby hypoxia. The stratification of patients with OSA according to AHI combined with ST 90 may allow better identification of prognostic information. Key Words: Obstructive sleep apnea, sleep time with oxygen saturation below 90%, hypoxia. Level of Evidence: 4 Laryngoscope, 125: , 2015 INTRODUCTION Obstructive sleep apnea (OSA) is a common syndrome characterized by repetitive episodic collapse of the upper airway and intermittent hypoxia during sleep. Disturbances in gas exchange lead to oxygen desaturation, hypercapnia, and sleep fragmentation, which contribute to the consequences of OSA including metabolic, neurocognitive, and cardiovascular effects. 1 The upper airway caliber is determined by afferent sensory input to the brainstem respiratory centers and efferent motor neural output to the upper airway structures. 2 Reestablishing airway patency in OSA is achieved due to arousal. The mucosal sensory receptor impairment in the upper airway might cause a delayed end-apneic arousal and extension of the apnea duration. 3 The longer the apnea duration is, the deeper the hypoxia becomes. The severity of OSA is stratified by the apneahypopnea index (AHI), which represents only the frequency of apneas and hypopneas per hour of sleep regardless of duration and morphology. 4 AHI does not completely reflect the pathophysiological characteristics or severity of hypoxia. 5 Moreover, patients with a similar AHI may have different clinical symptoms and outcomes. 6,7 Total sleep time with oxygen saturation below 90% (ST 90 ) is an objective parameter that can be easily obtained from polysomnography (PSG). In recent years, ST 90 has gained increasing attention in OSA research because of its direct relation to the duration and severity of hypoxia In the current study, we aimed to determine factors influencing ST 90 in the population referred to a tertiary sleep center for assessment of possible sleep-disordered breathing (SDB). From the Department of Otolaryngology Head and Neck Surgery (A.B., M.T.), and the Department of Biostatistics and Medical Informatics (S.B.), Akdeniz University School of Medicine, Antalya, Turkey. Editor s Note: This Manuscript was accepted for publication August 29, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Asli Bostanci, MD, Akdeniz University Hospital, H Blok K: 1, 07070, Konyaalti, Antalya, Turkey. draslibostanci@gmail.com DOI: /lary MATERIALS AND METHODS Study Design and Patients From November 2011 to February 2014, a total of 731 consecutive patients with suspected SDB, who underwent complete polysomnographic evaluation at our accredited sleep disorders center, were included into this retrospective analysis. Demographic and polysomnographic data as well as information regarding age, gender, body mass index (BMI), total sleep time, supine sleep time, percentage of supine sleep position,

2 nonsupine (lateral and prone) sleep time, percentage of nonsupine sleep position, sleep efficiency, sleep latency, arousal index, AHI, AHI supine, AHI rapid eye movement (AHI REM ), AHI non rapid eye movement (AHI NREM ), severity of SDB, longest apnea duration, mean obstructive apnea duration, total apnea duration, lowest O 2 saturation (SaO 2 ), mean SaO 2, mean O 2 desaturation, oxygen desaturation index (ODI), ST 90, and percentage of cumulative time with oxygen saturation below 90% (CT 90 ) were all recorded following institutional review board approval. Patients were excluded if they had central sleep apnea syndrome, previous treatment for SDB by continuous positive airway pressure, surgery, and/or oral device, age <18 or >70 years, serious cardiovascular disease, chronic obstructive pulmonary disease, asthma, neuropathy or active neurological disease, medications known to affect peripheral nerves, or malignancy. PSG (Compumedics E Series Profusion; Compumedics, Abbotsford, Victoria, Australia) was scored manually based on American Academy of Sleep Medicine 2007 criteria. 4 Apnea was defined as cessation of airflow for at least 10 seconds with continued effort (obstructive) or lack of effort (central) to breathe. Hypopnea was defined as a >50% decrease in a valid measure of airflow without a requirement for associated oxygen desaturation or arousal, and with a lesser airflow reduction in association with oxygen desaturation of >3%, or an arousal for at least 10 seconds. AHI was defined as the number of apnea and hypopnea occurrences per hour. An AHI of <5 was considered as normal or simple snoring, 5 to 15 as mild OSA, 15 to 30 as moderate OSA, and >30 as severe OSA. Statistical Analysis The primary outcome was the determination of factors influencing the ST 90. We expressed data as mean, standard deviation, median, range, and interquartile range for continuous variables. We reported binary variables as counts and percentages. First, bivariate correlation analyses were performed to assess relationships between ST 90 and other variables. Because normal distribution assumptions were not met, Spearman rho coefficients were calculated. The Mann-Whitney U test was utilized to evaluate the statistical significance of differences of ST 90 between the gender groups. After checking for multicollinearity (variance inflation factor < 5) and autocorrelation (Durbin-Watson test), explanatory variables with a marginal association with the ST 90 (P <.05) in the bivariate analysis were included in the multiple regression analysis. Stepwise regression was used to select the model that best explained the relationship between trans-st 90 and the change in explanatory variables. All P values were two-sided, with the level of significance set at <.05. All statistical analyses were performed by a professional biostatistician using IBM SPSS Statistics 20 software (IBM Corp., Armonk, NY). RESULTS Table I presents the characteristics of the patients. The median age was 48 years (range, years), and most patients were male (78.4%). The distributions of severity of SDB were as follows: normal/simple snoring, 18.2%; mild OSA, 25.6%; moderate OSA, 17.4%; and severe OSA, 38.9%. The median AHI, AHI supine, AHI REM, AHI NREM, arousal index, and ODI were 19, 36.7, 20.2, 18.6, 22.1, and 14 events/hour, respectively. The median oxymetric values of patients were as follows: lowest SaO 2, 83%; mean SaO 2, 95%; mean O 2 desaturation, 6%; longest apnea duration, 41.8 seconds; total apnea duration, 26.7 minutes; ST 90, 7 minutes; and CT 90, 1.8%. Table II presents univariate and multivariate linear regression analysis of factors influencing ST 90. The univariate analysis revealed a significant correlation between ST 90 and age (r ), BMI (r ), arousal index (r ), AHI (r ), mean SaO 2 (r ), and mean O 2 desaturation (r ), (P <.001 for all parameters). Furthermore, there was a significant, but weak, positive correlation between supine sleep position and ST 90 (r , P 5.008), and a significant, but quite weak, negative correlation between nonsupine sleep position and ST 90 (r , P 5.009). However, in multiple linear regression analysis, age (P <.001), BMI (P 5.040), male gender (P 5.001), AHI (P <.001), mean SaO 2 (P <.001), and mean O 2 desaturation (P <.001) remained to be independent parameters influencing ST 90 after adjustment for other confounders. Furthermore, these parameters explained a significant proportion of variance in ST 90 (R , F (6, 729) , P <.001). In addition, although there was a strong correlation between AHI and ST 90, a great variation of ST 90 values was observed, especially within the severe OSA group (Fig. 1). DISCUSSION OSA is characterized by episodic obstructions of airflow during sleep, with repetitive oscillations in oxyhemoglobin saturation. Conventionally, it was considered to be an anatomical pathology, because patients with OSA mostly have a narrow upper airway due to either increased soft tissue surrounding the airway or restricted craniofacial bone structure. 12,13 However, OSA can be encountered in patients with a normal anatomy, but may not be observed in patients with a narrow upper airway. 14 Currently, there is increasing evidence supporting that respiratory instability, low lung volume, low arousal threshold, and impaired neural regulation of breathing are significant contributors to the pathogenesis of apneas and hypopneas. 1 Regardless of underlying etiology, episodic collapse of the upper airway leads to chronic intermittent hypoxia (CIH), a hallmark of OSA, which triggers oxidative stress and chronic inflammation. 15,16 Consequently, all these pathophysiological processes give rise to detrimental effects on cardiovascular, neurocognitive, and metabolic functions. 1 The gold standard test for the diagnosis of OSA is the overnight PSG, with the primary outcome measure of AHI, which only indicates the number of apneas and hypopneas per hour. 4 However, AHI is incapable of reflecting the actual duration and severity of hypoxia, and disease outcome. Patients with similar AHI could have different cessation of breathing and oxygen desaturation characteristics regarding the duration and depth of events. These differences mostly affect the symptoms and consequences of the disorder. Mediano et al. reported that patients with excessive daytime sleepiness (EDS) had worse nocturnal oxygenation indices and longer apnea duration than those without EDS, despite the 1009

3 TABLE I. Characteristics of Patients. Variables No. (%) Median [Range], {IQR} Mean 6 SD Age, yr 48 [20 70], {16} Body mass index, kg/m [ ], {5.9} Gender, no. (%) Male 573 (78.4) Female 158 (21.6) Total sleep time, min 393 [ ], {70} Sleep efficiency, % 88.2 [ ], {12.7} Sleep latency, min 17.5 [1 175], {20} Arousal index, events/hr 22.1 [ ], {35.9} AHI, events/hr 19.0 [0 115], {39.0} AHI supine, events/hr 36.7 [0 120], {55.3} AHI REM, events/hr 20.2 [0 112], {44.3} AHI NREM, events/hr 18.6 [0 115], {40.8} Severity of sleep-disordered breathing, no. (%) Normal/simple snoring 133 (18.2) Mild OSA 187 (25.6) Moderate OSA 127 (17.4) Severe OSA 284 (38.9) Longest apnea duration, s 41.8 [ ], {34.8} Mean obstructive apnea duration, s 19.6 [0 55.4], {9.5} Total apnea duration, min 26.7 [ ], {83.3} Lowest SaO 2,% 83 [38 96], {12} Mean SaO 2,% 95 [88 99], {2} Mean O 2 desaturation, % 6 [2 26], {4} ODI, events/hr 14.0 [ ], {27.0} ST 90, min 7.0 [0 427], {40} CT 90,% 1.8 [0 93], {10} AHI 5 apnea hypopnea index; CT 90 5 percentage of cumulative sleep time with oxygen saturation below 90%; IQR 5 interquartile range; NREM 5 non rapid eye movement; ODI 5 oxygen desaturation index; OSA 5 obstructive sleep apnea; REM 5 rapid eye movement; SaO 2 5 O 2 saturation; SD 5 standard deviation; ST 90 5 total sleep time with oxygen saturation below 90%. fact that neither the AHI, arousal indices, nor overall sleep architecture were significantly different between groups. 6 In a study evaluating the validity of a new index considering factors such as the duration and degree of hypoxia the so called integrated area of desaturation (IAD) Asano et al. reported that patients who experienced cardiovascular events had significantly higher IAD regardless of AHI. 7 Recently, in a similar TABLE II. Univariate and Multivariate Linear Regression Analysis of Factors Influencing Sleep Time With Oxygen Saturation Below 90%. Univariate Analysis Multiple Linear Regression Analysis Variables Median (IQR) r P Coefficients 95% CI P Age, yr 48 (16) < to <.001 Body mass index, kg/m (5.9) < to Gender, male/female, no. (%) 9 (49)/3 (17) < to Arousal index, events/hr 22.1 (35.9) < AHI, events/hr 19 (39) < to <.001 Mean SaO 2, % 95 (2) < to <.001 Mean O 2 desaturation, % 6 (4) < to <.001 Supine sleep position, % 43.7 (41.4) Nonsupine sleep position, % 56.4 (41.7) % CI 5 95% confidential interval; AHI 5 apnea-hypopnea index; IQR 5 interquartile range; SaO 2 5 O 2 saturation. 1010

4 Fig. 1. Distributions of sleep time with oxygen saturation below 90% (ST 90 ) values within different apnea-hypopnea index (AHI) severity categories. OSA 5 obstructive sleep apnea. study with a median follow-up time of 183 months, Kulkas et al. reported that despite there being no significant differences in AHI, patients with higher duration of obstruction and desaturation had increased mortality. 5 CIH is usually defined as repeated episodes of hypoxia interspersed with periodic reoxygenations. 17 Currently, there is no universally accepted quantitative clinical test to measure the intensity and/or severity of CIH due to the lack of a more precise definition. The ST 90 is an objective parameter that represents the duration of nocturnal hypoxia. Li et al. 8 first investigated the clinical value of ST 90 in the evaluation of CIH in patients with OSA and demonstrated that the correlation coefficients of ST 90 with AHI and with the Epworth Sleepiness Scale were both much higher than those of the lowest SaO 2. Later, Li and Jin noted that ST 90 was strongly correlated with AHI and total apnea duration (r and 0.776, respectively). 9 Recently, Zhang et al. demonstrated that after adjustment for BMI and other cardiovascular risk factors, the ST 90 was the strongest independent predictor of high-sensitivity C- reactive protein elevation, which is known to be associated with the severity of OSA. 10 They concluded that the severity of OSA should be stratified by combining AHI and nocturnal CIH variables, such as ST 90 and ODI, instead of AHI alone. Furthermore, in a study of 119 OSA patients who underwent velopharyngeal surgery, including uvulopharyngopalatoplasty with transpalatal advancement pharyngoplasty, the ST 90 rather than AHI was reported to be one of the independent predictors of surgical success. 11 The current study is the largest sample to date that examines the relationship between various polysomnographic variables and ST 90 in a population with suspected SDB. Our results demonstrated that ST 90 is independently influenced by age, BMI, male gender, AHI, mean SaO 2, and mean O 2 desaturation, each explaining a significant proportion of variance. The study results also provide supporting evidence that patients with similar AHI may have very different values of ST 90, and thereby hypoxia. Potential limitations of our study include its retrospective nature, with inherent problems of selection bias, an that it is a single-institution analysis, which could lead to referral bias. A lack of follow-up data and lack of analysis of other potential confounders, such as anthropometric measurements, comorbidities, smoking, and inflammatory markers, could also be considered potential limitations. CONCLUSION The current study contributes to increased concerns regarding failure of AHI in reflecting the actual severity of OSA. Based on our results and available data in the literature, the stratification of patients with OSA according to the AHI combined with ST 90 may allow better identification of prognostic information and selection of individualized patient-tailored treatment modalities. Future randomized controlled trials with longer followup are needed to confirm these findings. BIBLIOGRAPHY 1. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014;383: Guilleminault C, Ramar K. Neurologic aspects of sleep apnea: is obstructive sleep apnea a neurologic disorder? Semin Neurol 2009;29: Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164: Iber C, Ancoli-Israel S, Chesson A, Quan S. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Westchester, IL: American Academy of Sleep Medicine; Kulkas A, Tiihonen P, Julkunen P, Mervaala E, T oyr as J. Novel parameters indicate significant differences in severity of obstructive sleep apnea with patients having similar apnea-hypopnea index. Med Biol Eng Comput 2013;51:

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