Nocturnal Intermittent Hypoxia Research Articles

The Association between the Phenotype of Excessive Daytime Sleepiness and Blood Pressure in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome

Objective Investigate the clinical features and the blood pressure (BP) pattern of the phenotype of excessive daytime sleepiness (EDS) in OSAHS.Methods A total of 508 Chinese adults with suspected OSAHS were referred to our sleep laboratory from October 2009 to May 2012. On the same night of polysomnography (PSG), the levels of blood pressure were measured before sleeping (bedtime BP) and immediately after waking up in the next morning (morning BP). EDS was recognized as Epworth Sleepiness Scale (ESS)≥9. Subjects were classified into four groups based on the apnea-hypopnea index (AHI) from PSG as follows: control (simple snoring) group (control, n=104) with AHI<5; mild group (mild, n=89) with AHI≥5 and <15; moderate group (moderate, n=70) with AHI≥15 and<30; and severe group (severe, n=245) with AHI ≥30. The differences and correlations between BP and PSG parameters in EDS and non-EDS group of OSAHS patients were analyzed.Results In all subjects, ESS was positively correlated with morning diastolic blood pressure (DBP), Mean arterial pressure (MAP) and bedtime DBP (r=0.144, 0.102 and 0.114, respectively, each P value<0.05). In OSAHS patients, ESS was only positively correlated with morning DBP (r=0.137, P<0.05). OSAHS patients with EDS phenotype were younger and were more likely to have the symptom of waking up feeling tired (36.1% vs. 23.2%, p=0.023), who had lower MSaO2, longer SIT90 (the ratio of time of SpO2 below 90% in total sleep time) and higher DBP (bedtime as well as morning). In patients with AHI≥15, ESS was correlated positively with both bedtime and morning DBP after controlling the confounding effects of age, sex, BMI, AHI and nadir nocturnal oxygen saturation( r=0.126,0.143, respectively, both P values<0.05). And in OSAHS patients of EDS phenotype, the bedtime DBP, bedtime MAP, morning DBP, and morning MAP were 3~5 mm Hg higher than that in patients of non-EDS phenotype(P<0.05). In the moderate and severe OSAHS group, patients with EDS phenotype were younger and had a lower mean blood oxygen saturation (MSaO2), longer time of SpO2 below 90% and higher SIT90 than patients with non-EDS phenotype (P<0.05). In hypertensive OSAHS patients, patients with EDS were also younger and had higher micro-arousal index (MiI), as well as higher morning DBP, morning MAP and bedtime DBP than that in non-EDS group (P<0.05).Conclusions EDS in OSAHS patients is a special phenotype, which was characterized by younger age, higher DBP and more severe hypoxic load. This feature is mainly manifested in moderate and severe OSAHS patients. It is very important to identify the phenotype of EDS in patients with OSAHS, who may meet more benefits from effective treatment of OSAHS by correcting the intermittent nocturnal hypoxia and sleep fragmentation.

Nocturnal intermittent hypoxia as an associated risk factor for microalbuminuria in women with type 2 diabetes mellitus

Introduction The International Diabetes Federation has expressed the need for further research into the links between sleep-disordered breathing (SDB) and type 2 diabetes mellitus. However studies on the association between SDB and microvascular complications among type 2 diabetes (T2DM) mellitus patients are limited. Materials and methods We recruited 513 Japanese patients with T2DM. Nocturnal intermittent hypoxia was diagnosed using the 3% oxygen desaturation index (ODI), with Results The prevalence of nocturnal intermittent hypoxia was 45.4% among T2DM patients. The nocturnal intermittent hypoxia group was older (P = 0.007), had a higher BMI (P = 0.001), greater weight change since the age of 20 years (P = 0.001), higher smoking rate (P = 0.005), and increased prevalence of hypertension (P = 0.001), hyperlipidaemia (P = 0.001), microalbuminuria (P = 0.001), and nephropathy (P = 0.001). Microalbuminuria (model 1: OR, 3.41; 95% CI, 1.85–6.40; P = 0.001; model 2: OR, 3.69, 95% CI, 1.85–7.59, P = 0.001; model 3: OR, 3.12; 95% CI, 1.45–6.95; P = 0.001) and nephropathy (model 1: OR, 3.12; 95% CI, 1.45–6.95; P = 0.001; model 2: OR, 7.31; 95% CI, 2.11–31.6; P = 0.001; model 3: OR, 5.23; 95% CI, 1.45–23.8; P = 0.001) were derived as factors from all 3 statistical models and constantly associated with nocturnal intermittent hypoxia only in women. Conclusion Nocturnal intermittent hypoxia was highly prevalent among T2DM patients, and may be an independent associated risk factor for microalbuminuria in Japanese women with T2DM. Acknowledgements We thank Isao Saito, Shin Yamamoto, Teruki Miyake, Teruhisa Ueda, Tetsuji Niiya, Masamoto Torisu, Teru Kumagi, Takenori Sakai, Hisaka Minami, Hiroaki Miyaoka, Susumu Sakurai, Bunzo Matsuura, and Morikazu Onji. This study was supported in part by Grants-in-Aid for Young Scientists (B) (grant number 217090583, 2008–2010) provided to SF from the Japanese Society for the Promotion of Science.

S118 The ventilatory response to CO2 within obstructive sleep apnea patients

IntroductionObstructive Sleep Apnea (OSA) is a condition defined by the collapse of the upper airway and cessation of respiration during sleep. The resulting hypoventilation leads to intermittent nocturnal hypoxia and...

Nocturnal Intermittent Hypoxia Is Independently Associated with Pain in Subjects Suffering from Sleep-disordered Breathing

On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation. After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports. Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001). Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

Plasma leptin and vascular endothelial growth factor (VEGF) in normal subjects at high altitude (5050 m)

Context: High altitude (HA) is a model of severe hypoxia exposure in humans. We hypothesized that nocturnal hypoxemia or acute maximal exercise at HA might affect plasma leptin and VEGF levels. Objectives: Plasma leptin, VEGF and other metabolic variables were studied after nocturnal pulse oximetry and after maximal exercise in healthy lowlanders on the 3rd-4th day of stay in Lobuche (5050 m, HA) and after return to sea level (SL). Results: Leptin was similar at SL or HA in both pre- and post-exercise conditions. Pre-exercise VEGF at HA was lower, and cortisol was higher, than at SL, suggesting that nocturnal intermittent hypoxia associated with periodic breathing at HA might affect these variables. Conclusions: Leptin levels appear unaffected at HA, whereas nocturnal hypoxic stress may affect plasma VEGF. Future HA studies should investigate the possible role of nocturnal intermittent hypoxemia on metabolism.

Nocturnal intermittent hypoxia as an associated risk factor for microalbuminuria in Japanese patients with type 2 diabetes mellitus

We estimated the prevalence of nocturnal intermittent hypoxia, a surrogate marker of obstructive sleep apnoea, among type 2 diabetes mellitus (T2DM) patients and examined the association between nocturnal intermittent hypoxia and microvascular diseases. We recruited 513 Japanese patients (292 men and 221 women) with T2DM. Nocturnal intermittent hypoxia was diagnosed using the 3% oxygen desaturation index, with less than five events per hour corresponding to normal and five events or more per hour corresponding to nocturnal intermittent hypoxia. The prevalence of nocturnal intermittent hypoxia was 45.4% among T2DM patients. The nocturnal intermittent hypoxia group was older and had a higher BMI, greater weight change since the age of 20 years, higher smoking rate and increased prevalence of hypertension, hyperlipidaemia, microalbuminuria and macroalbuminuria. Microalbuminuria (model 1: odds ratio (OR), 3.41; 95% CI, 1.85-6.40; model 2: OR, 3.69; 95% CI, 1.85-7.59 and model 3: OR, 3.12; 95% CI, 1.45-6.95) and nephropathy (model 1: OR, 4.51; 95% CI, 1.58-15.1; model 2: OR, 7.31; 95% CI, 2.11-31.6 and model 3: OR, 5.23; 95% CI, 1.45-23.8) were derived as factors from all the three statistical models and constantly associated with nocturnal intermittent hypoxia only in women. Nocturnal intermittent hypoxia was highly prevalent among T2DM patients and may be an independent associated risk factor for microalbuminuria in Japanese women with T2DM.

Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia.

BackgroundBoth obstructive sleep apnea (OSA) and a novel lipocalin, neutrophil gelatinase associated lipocalin (Ngal), have been reported to be closely linked with cardiovascular disease and loss of kidney function through chronic inflammation. However, the relationship between OSA and Ngal has never been investigated.ObjectivesTo evaluate the relationship between Ngal and OSA in clinical practice.MethodsIn 102 patients, polysomnography was performed to diagnose OSA and plasma Ngal levels were measured. The correlations between Ngal levels and OSA severity and other clinical variables were evaluated. Of the 46 patients who began treatment with continuous positive airway pressure (CPAP), Ngal levels were reevaluated after three months of treatment in 25 patients.ResultsThe Ngal level correlated significantly with OSA severity as determined by the apnea hypopnea index (r = 0.24, p = 0.01) and 4% oxygen desaturation index (ODI) (r = 0.26, p = 0.01). Multiple regression analysis showed that the Ngal level was associated with 4%ODI independently of other clinical variables. Compliance was good in 13 of the 25 patients who used CPAP. Although the OSA (4%ODI: 33.1±16.7 to 1.1±1.9/h, p<0.01) had significantly improved in those with good compliance, the Ngal levels were not significantly changed (60.5±18.1 before CPAP vs 64.2±13.9 ng/ml after CPAP, p = 0.27).ConclusionsPlasma Ngal levels were positively associated with the severity of OSA. However, the contribution rate of OSA to systemic Ngal secretion was small and changes in Ngal levels appeared to be influenced largely by other confounding factors. Therefore, it does not seem reasonable to use the Ngal level as a specific biomarker of OSA in clinical practice.

P260 Haematological characteristics of patients referred for investigation of Obstructive Sleep Apnoea

IntroductionObstructive Sleep Apnoea (OSA) is a condition with increasing prevalence. Individuals with severe OSA have significant intermittent nocturnal hypoxia. Erythropoiesis is stimulated through the renal secretion of erythropoietin in response...

Excessive daytime sleepiness in sleep disorders.

Excessive daytime sleepiness is a significant public health problem, with prevalence in the community estimated to be as high as 18%. Sleepiness is caused by abnormal sleep quantity or sleep quality. Amongst others, multiple neurological, psychological, cardiac and pulmonary disorders may contribute. Risk factors for excessive sleepiness include obesity, depression, extremes of age and insufficient sleep. In the clinical setting, two of the most commonly encountered causes are obstructive sleep apnoea and periodic limb movement disorder. There is continuing discussion of the mechanisms by which these disorders cause daytime symptoms, with intermittent nocturnal hypoxia, sleep fragmentation and autonomic dysregulation identified as important factors. The increased prevalence of obstructive sleep apnoea in obese subjects does not fully account for the increased rates of daytime sleepiness in this population and there is evidence to suggest that it is caused by metabolic factors and chronic inflammation in obese individuals. Sleepiness is also more common in those reporting symptoms of depression or anxiety disorders and significantly impacts their quality of life. Clinicians should be aware of factors which put their patients at high risk of daytime sleepiness, as it is a debilitating and potentially dangerous symptom with medico-legal implications. Treatment option should address underlying contributors and promote sleep quantity and sleep quality by ensuring good sleep hygiene. However, stimulant medication may be indicated in some cases to allow for more normal daytime functioning.

Less variation of R-R interval of electrocardiogram in nonobese type 2 diabetes with nocturnal intermittent hypoxia

Obesity is a major risk factor for sleep-disordered breathing (SDB). However, many Japanese subjects with diabetes are less obese despite compared with Caucasian. We evaluated the relationship between SDB and clinical characteristics other than obesity, especially in relation to cardiac autonomic neuropathy (CAN) in Japanese subjects with diabetes. The study included a total of 261 consecutive Japanese subjects with type 2 diabetes, including nonobese subjects defined as BMI <25 kg/m² for Japanese. SDB was screened by 4% oxygen desaturation index (ODI) level of 5 or more events per hour, which was measured by nocturnal pulse oximetry. CAN was examined with the variation of R-R intervals (CVRR). The SDB were found in 24.5% of total subjects and 16.3% of nonobese subjects with type 2 diabetes, respectively. The nonobese type 2 diabetes subjects with SDB had significantly lower coefficient of CVRR than those without SDB. Multiple regression analysis revealed that BMI and heart rate were significant independent factors for SDB in total subjects with type 2 diabetes, but CVRR was the only significant independent factor for SDB in nonobese subjects with type 2 diabetes. These findings suggest that the presence of SDB should be kept in mind in type 2 diabetic patients with abnormality in CVRR variation in electrocardiogram even though they are not obese.

Sleep-Disordered Breathing is Associated with Asthma Severity in Children

To examine the relationships among obesity, sleep-disordered breathing (SDB, defined as intermittent nocturnal hypoxia and habitual snoring), and asthma severity in children. We hypothesized that obesity and SDB are associated with severe asthma at a 1- year follow-up. Children aged 4-18 years were recruited sequentially from a specialty asthma clinic and underwent physiological, anthropometric, and biochemical assessment at enrollment. Asthma severity was determined after 1 year of follow-up and guideline-based treatment, using a composite measure of level of controller medication, symptom burden, and health care utilization. Multivariate logistic regression was used to examine adjusted associations of SDB and obesity with asthma severity at 12-month follow-up. Among 108 subjects (mean age, 9.1±3.4 years; 45.4% African-American; 67.6% male), obesity and SDB were common, affecting 42.6% and 29.6% of subjects, respectively. After adjusting for obesity, race, and sex, children with SDB had a 3.62-fold increased odds of having severe asthma at follow-up (95% CI, 1.26-10.40). Obesity was not associated with asthma severity. SDB is a modifiable risk factor for severe asthma after 1 year of specialty asthma care. Further studies are needed to determine whether treating SDB improves asthma morbidity.

The Effect of Heart Rate Response to Nocturnal Intermittent Hypoxia in Obstructive Sleep Apne

PURPOSE: It has been well known that the patients with long duration of type2 diabetes mellitus (DM) frequently suffer from autonomic nerve dysfunction. The activity of the autonomic nervous system under the condition of nocturnal intermittent hypoxia may alter the pathophysiology of obstructive sleep apnea (OSA). Our objective was to investigate the characteristics of OSA with and without DM.

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice

RationaleObstructive sleep apnea results in nocturnal intermittent hypoxia (IH) as a main trigger for cardiovascular morbidity, including atherosclerosis. IH induces hemodynamic, hormono-metabolic and also immuno-inflammatory alterations that could differentially contribute to atherosclerosis. Our study aimed at examining their respective contribution to the proatherogenic role of IH in atherosclerosis-prone mice. MethodsFifteen-week-old male apolipoprotein E-deficient (ApoE−/−) mice fed on a high-cholesterol diet (HCD) for 6 weeks and exposed for the last 14 days to IH (21–5% FiO2, 60s cycle, 8h/day) or air, were investigated for aortic atherosclerosis and lipid alterations. Then IH proatherogenicity was assessed in 15- and 20-week-old ApoE−/− mice fed on a standart-chow diet (SCD) exposed to IH or air for 14 days and assessed for atherosclerosis, lipid, hemodynamic and inflammation alterations. ResultsIH aggravated atherosclerosis in HCD-fed mice, whereas the extremely high cholesterol levels due to HCD were not different between normoxic and hypoxic animals. In SCD-fed mice, IH also aggravated atherosclerosis, more severely in 20 compared to 15-week-old animals. However, cholesterol levels that increased with IH were not different in the two SCD-fed groups. IH slightly elevated arterial blood pressure in 20-week-old animals only, and induced systemic and vascular inflammation, including increased splenocyte proliferation with decreased IL-10 secretion, and increased T-lymphocytes within atherosclerotic plaques. ConclusionsA short IH exposure without HCD has proatherogenic effects. In contrast to blood pressure or plasma lipids which were slightly or inconstantly affected by IH, inflammation at systemic and vascular levels appears as a potential contributing factor to IH atherogenicity.

P2-302 Nocturnal intermittent hypoxia and cardiovascular risk factors in community-dwelling Japanese: the Circulatory Risk in Communities Study (CIRCS)

IntroductionTo investigate whether nocturnal intermittent hypoxia (NIH), a surrogate marker for sleep apnoea, is associated with cardiovascular risk factors, we conducted epidemiological studies.MethodsThe CIRCS is a prospective cohort study across...

Obstructive sleep apnea: its prevention and screening may contribute to the prevention of hypertension, diabetes and cardiovascular diseases

Relationships between obstructive sleep apnea and cardiovascular diseases have been reported by both clinical and epidemiological studies. To investigate whether nocturnal intermittent hypoxia (NIH), a surrogate marker for obstructive sleep apnea in the general population, is associated with cardiovascular risk factors, we have conducted epidemiological studies in Japan. The Circulatory Risk in Communities Study (CIRCS) is a cohort study conducted across Japan to examine the risk factors for cardiovascular diseases. In CIRCS participants, NIH was estimated by the hourly occurrences of oxygen desaturation ≥3% (3% oxygen desaturation index [3% ODI]) measured during sleep using a pulse-oximeter. Our studies showed that among middle-aged Japanese, 3% ODI levels were associated with hypertension, elevated serum CRP levels, accumulation of metabolic risk factors, and increased risk of developing type 2 diabetes. Screening for obstructive sleep apnea in the general population is a promising and widely broadly applicable strategy for predictive, preventive and personalized medicine.

Promoting predictive, preventive and personalized medicine in treatment of cardiovascular diseases

Promoting predictive, preventive and personalized medicine in treatment of cardiovascular diseases

Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17-24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr (n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 +/- 1.3 vs. 74 +/- 1.7 mmHg, P < 0.01), MSNA [9.94 +/- 2.0 to 14.63 +/- 1.5 bursts/min (P < 0.05); 16.89 +/- 3.2 to 26.97 +/- 3.3 bursts/100 heartbeats (hb) (P = 0.01)], and forearm vascular resistance (FVR) (35.3 +/- 5.8 vs. 55.3 +/- 6.5 mmHg x ml(-1) x min x 100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans

Obstructive sleep apnoea syndrome (OSAS) causes nocturnal chronic intermittent hypoxia (IH) that contributes to excess cardiovascular morbidity. To explore the consequences of IH, we used our recently developed model of nocturnal IH in healthy humans to characterise the profile of this blood pressure increase, to determine if it is sustained and to explore potential physiological mechanisms. We performed 24-h ambulatory monitoring of blood pressure in 12 healthy subjects before and after 2 weeks of IH exposure. We also assessed systemic haemodynamics, muscle sympathetic nerve activity (MSNA), ischaemic calf blood flow responses and baroreflex gain. We obtained blood samples for inflammatory markers before, during and after exposure. IH significantly increased daytime ambulatory blood pressure after a single night of exposure (3 mmHg for mean and diastolic) and further increased daytime pressures after 2 weeks of exposure (8 mmHg systolic and 5 mmHg diastolic). Mean ± sd MSNA increased across the exposure (17.2 ± 5.1 versus 21.7 ± 7.3 bursts·min⁻¹; p < 0.01) and baroreflex control of sympathetic outflow declined from -965.3 ± 375.1 to -598.4 ± 162.6 AIU·min⁻¹ ·mmHg⁻¹ (p < 0.01). There were no evident changes in either vascular reactivity or systemic inflammatory markers. These data are the first to show that the arterial pressure rise is sustained throughout the waking hours beyond the acute phase immediately after exposure. Moreover, they may suggest that sympathoactivation induced by IH likely contributes to blood pressure elevation and may derive from reduced baroreflex inhibition. These mechanisms may reflect those underlying the blood pressure elevation associated with OSAS.

Nocturnal intermittent hypoxia and C reactive protein among middle-aged community residents: a cross-sectional survey

BackgroundThere are conflicting results for the association between obstructive sleep apnoea and raised C reactive protein (CRP) levels. A study was undertaken to investigate whether nocturnal intermittent hypoxia, a surrogate...

Nocturnal Intermittent Serious Hypoxia and Reoxygenation in Proliferative Diabetic Retinopathy Cases

To clarify the relationship between evaluation items of sleep-disordered breathing and diabetic retinopathy in detail. Cross-sectional comparative study. Sixty-eight consecutive nonproliferative diabetic retinopathy and 151 proliferative diabetic retinopathy (PDR) cases who had undergone surgeries in our department were included in this study. Pulse oximetry was conducted overnight and mean oxygen saturation by pulse oximeter (SpO(2); %), the sleeping 4% oxygen desaturation index (4% ODI times/hour), lowest SpO(2) (%), and the cumulative percent time spent at SpO(2) < 90% (CT 90%) were calculated. The results were evaluated and compared between the 2 groups. In addition, these results and preoperative patient background factors were analyzed using logistic regression analysis to clarify risk factor of PDR. 4% ODI and CT 90% in the PDR group were significantly higher than in the nonproliferative diabetic retinopathy group (4% ODI, 7.8 vs. 4.9; P = .007; CT 90%, 2.2 vs 0.8; P = .0006). Lowest SpO(2) was significantly lower in the PDR group than in the nonproliferative diabetic retinopathy groups (82.4 vs 87.0; P = .0006). Logistic regression analysis identified being younger, having a lower value for the lowest SpO(2), and a high hemoglobin A1c value to be risk factors for PDR (age: odds ratio, 0.90; 95% confidence interval, -0.86 to -0.94; P < .0001; lowest SpO(2): odds ratio, 0.93; 95% confidence interval, 0.88 to 0.99; P = .02; hemoglobin A1c: odds ratio, 1.00 to 1.69; P = .047). This study indicated that PDR cases had episodes of nocturnal intermittent hypoxia and reoxygenation as a result of sleep-disordered breathing and that low-value lowest SpO(2) were the risk factors for PDR development.