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Kulkas, Antti, Duce, Brett, Leppanen, Timo, Hukins, Craig, & Toyras, Juha(2017)Severity of desaturation events differs between hypopnea and obstructiveapnea events and is modulated by their duration in obstructive sleep ap-nea.Sleep and Breathing, 21(4), pp. 829-835.

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1 2 Severity of desaturation events differs between hypopnea and obstructive apnea events and is modulated by their 3

duration in obstructive sleep apnea 4

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1,2Kulkas Antti PhD, 3,4Duce Brett BSc, 1,2Leppänen Timo PhD, 6

3Hukins Craig MBBS FRACP, 2,5Töyräs Juha PhD 7

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1Department of Clinical Neurophysiology, Seinäjoki Central Hospital, Seinäjoki, Finland 9

2Department of Applied Physics, University of Eastern Finland, Kuopio, Finland 10

3Sleep Disorders Centre, Department of Respiratory & Sleep Medicine, Princess Alexandra Hospital, Brisbane, 11 Australia 12

4Faculty of Science and Engineering, Queensland University of Technology, Brisbane, Australia 13

5Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland 14

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Corresponding Author: Chief Physicist, Adjunct Professor Antti Kulkas, Ph.D., Department of Clinical 18

Neurophysiology, Seinäjoki Central Hospital, Hanneksenrinne 6, 60220 Seinäjoki, Finland, [email protected], fax: 19

+35864154037 , tel: +35864154547 20

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mailto:[email protected]

ABSTRACT 32

Purpose: Frequency of apnea and hypopnea events is used to estimate the severity of obstructive sleep apnea (OSA). 33

However, comprehensive information on whether apneas and hypopneas cause an equal biological effect is not available. 34

The purpose of the present work was to evaluate the effect of the breathing cessation event type (i.e. obstructive apnea or 35

hypopnea) and duration on the severity of related SpO2 desaturation events. 36

Methods: Type 1 polysomnograms of 395 patients (220 males and 175 females) examined for suspected OSA were 37

analyzed. Desaturation severity related to hypopnea and obstructive apnea events were compared and comparison was 38

controlled for gender, sleep stage, sleeping position, age and body mass index. Hypopneas and obstructive apneas were 39

further divided into eight different durational categories and related desaturation event characteristics were compared 40

between the groups. 41

Results: SpO2 desaturation events caused by obstructive apneas were statistically significantly (p≤0.004) longer, greater 42

in area and deeper compared to the SpO2 desaturations caused by hypopneas. The increase in the duration of hypopnea 43

and obstructive apnea events led to increase in the duration and area of related SpO2 desaturations. The increase in the 44

obstructive apnea event duration also led to increase in the depth of related desaturation event. 45

Conclusions: Obstructive apneas led to more severe SpO2 desaturation compared to hypopneas. Increased event duration 46

led to increase in the severity of the related SpO2 desaturation. In addition to considering event duration, obstructive 47

apneas should have more weight than hypopneas when estimating severity of OSA and associated long-term 48

cardiovascular risk. 49

Keywords: Sleep disordered breathing, desaturation severity, desaturation area, apnea hypopnea index, severity 50

estimation 51

52

INTRODUCTION 53

Obstructive sleep apnea (OSA) is a highly prevalent sleep related breathing disorder associated with severe health 54

consequences [1, 2]. It is characterized by repetitive complete (apnea) or partial (hypopnea) breathing cessations during 55

sleep [3–5]. The most common index used in the diagnosis and severity classification of OSA is the Apnea-Hypopnea 56

Index (AHI) calculated as the number of apnea and hypopnea events per hour of sleep [3]. Despite its widespread use, 57

there is only poor correlation between AHI and complications (quality of life [6], blood pressure [7], depression and 58

anxiety [8], and treatment response [9]) typically associated with OSA. 59

Two of the most glaring issues associated with AHI are the way in which it deals with event type and event duration. 60

According to the conventional computation of AHI, both apnea and hypopnea events have the same weighting when the 61

severity of OSA is estimated. Despite the paucity of studies examining the physiological differences between apneas and 62

hypopneas, we assume that the physiological impact of a hypopnea is not identical to that of an apnea. In short, a period 63

of no airflow should elicit greater detriments than a similar of period with reduced airflow. 64

Besides the minimum event duration requirement of 10 s AHI does not consider the duration of individual events. 65

However, it is known that the durations of individual hypopnea and apnea events show significant variation between 66

patients with similar AHI [10]. The consequences of a 60 second apnea are probably not the same as consequences of a 67

10 second apnea [11, 12]. It logically follows that the duration of the individual breathing cessation events is a factor that 68

should be considered when estimating the overall severity of OSA [11–14]. This is supported by preliminary findings 69

showing that more detailed analysis of breathing cessations and desaturation events can improve the risk estimation of 70

mortality and morbidity related to OSA [13, 14]. 71

Intermittent hypoxemia associated with apneas and hypopneas in sleep is an important consequence of OSA [15]. There 72

is some evidence that longer apneas are related to more severe desaturations compared to shorter ones [16–18]. Higher 73

body mass index (BMI), age, supine sleeping position, male gender, rapid eye movement (REM) sleep and event type 74

(apnea compared to hypopnea) have been shown to increase the depth of desaturations [19]. Besides the depth the duration 75

and area of the desaturation may be considered to affect the severity of the desaturation event as well. Probably longer 76

desaturations have more severe consequences compared to shorter ones. Nonetheless, the evidence whether obstructive 77

apneas are more detrimental compared to hypopneas is limited [12]. 78

The aim of this work was to evaluate the effect of breathing cessation event type (i.e. obstructive apnea or hypopnea) and 79

duration on the severity (duration, area and depth) of related desaturation event. We hypothesize that hypopneas lead to 80

milder desaturation events than obstructive apneas and that longer hypopnea and obstructive apnea events cause more 81

severe desaturations (greater in duration, area and depth), which should be considered when assessing the cardiovascular 82

risk related to OSA. 83

84

METHODS 85

Type 1 diagnostic polysomnographies (PSG) of 395 patients examined for suspected OSA (220 males and 175 females) 86

were analyzed retrospectively. These PSGs were recorded at the Princess Alexandra Hospital, Brisbane, Australia. A 87

patient was excluded if the total sleep time was less than two hours, if a split night treatment protocol (from diagnostic to 88

positive airway pressure (PAP) therapy) was implemented, a primary PSG channel (nasal pressure, pulse oximetry, all 89

electroencephalography (EEG), respiratory effort, body position) contained too much artifact for reliable analysis or if 90

supplemental oxygen was given during the PSG. 91

Polysomnography 92

PSGs were recorded with Compumedics Grael acquisition devices (Compumedics, Abbotsford, Australia). The recording 93

montage comprised of EEG (F4-M1, C4-M1, O2-M1), left and right electro-oculogram (EOG) (recommended derivation: 94

E1-M2, E2-M2), chin electromyogram (EMG, mental/submental positioning), modified lead II electrocardiogram (ECG), 95

nasal pressure (DC amplified), oronasal thermocouple, body position, thoracic and abdominal respiratory effort (inductive 96

plethysmography), pulse oximetry (Nonin Xpod 3011), left and right leg movement (anterior tibialis EMG) and sound 97

pressure level (dBA meter: Tecpel 332). PSGs were de-identified and all previous respiratory event scorings were 98

removed. PSGs were then manually rescored by two scorers with Compumedics Profusion 4.0 (Build 410) software in 99

random order using the AASM2012 criteria [5]. Both of the scorers have over 15 years’ experience in scoring PSGs and 100

participate regularly in intra- and inter-laboratory scoring concordance activities. Randomization of PSG’s was performed 101

using the freely accessible Randomizer website [20]. 102

Data Analysis 103

An apnea was manually scored based on the current definition of the cessation of breathing (≥90% reduction in oronasal 104

thermal sensor signal) for 10 seconds or longer and a hypopnea was manually scored when ≥30% reduction in airflow 105

(nasal pressure) for 10 seconds or longer resulting ≥3% decrease in SpO2 or electroencephalogram (EEG) based arousal 106

was witnessed [5]. Central and mixed apneas were excluded from the further analysis. Hypopnea and obstructive apnea 107

event data and related ≥3% SpO2 desaturation event data from all patients were collected and included into the analysis. 108

Hypopneas followed by arousals (but not desaturation) and obstructive apneas that were not followed by desaturation 109

events were excluded from the analysis. The first desaturation event inside a 60-s window from the beginning of the 110

hypopnea or obstructive apnea event was linked to the hypopnea or obstructive apnea [13, 14]. A desaturation event was 111

visually determined to start at the first baseline point of the oxygen saturation signal before the onset of the drop and end 112

at the point when the signal returns to the baseline. In cases where baseline was not reached the end point was determined 113

visually at the start of plateau after the desaturation. The duration of the desaturation was calculated between the start and 114

end points. The interval between the start and end points was further divided into several bins where the width was 115

determined by the sampling interval (0.0625s). The height of each bin was calculated as the difference between the oxygen 116

saturation value at the first baseline point and the oxygen saturation value within the bin in question. The area (s%) of 117

each desaturation event was further calculated as the sum of the areas of these bins. An example of the desaturation event 118

characteristics is shown in figure 1. 119

Obstructive apnea and hypopnea events were divided into eight different categories based on their duration: 10 to ≤15s, 120

15 to ≤20s, 20 to ≤25s, 25 to ≤30s, 30 to ≤35s, 35 to ≤40, 40 to ≤45s and >45s. All events with duration exceeding 45s 121

were collected into one category as the number of these events was limited and could not reasonably be further divided 122

into smaller categories. The durations, depths and areas of the related desaturation events were then compared within each 123

durational category between obstructive apnea and hypopnea events. Furthermore, it was investigated whether duration 124

of hypopneas or obstructive apneas modulate the durations, areas and depths of the associated desaturations events. 125

Statistical Analysis 126

Statistical significance of the differences in the severity of desaturations between the event types was tested with Mann-127

Whitney U test. Spearman correlation analyses were performed to investigate the relationship between the duration of 128

hypopneas and obstructive apneas with respect to the duration, area and depth of the related desaturation events. Kruskal-129

Wallis pairwise comparison was applied to estimate the differences between different durational categories. Mixed model 130

analysis adjusted for gender, sleep stage (NREM vs. REM), sleeping position (non-supine vs. supine), age and BMI was 131

performed to assess differences in the severity of desaturation events associated with hypopneas or obstructive apneas. 132

Before the mixed model analysis, hypopnea and obstructive apnea event durations and associated desaturation event 133

durations, areas and depths were transformed logarithmically to achieve a normal distribution of the corresponding model 134

residuals and the transformed variables were further standardized. The normality of the model residuals was visually 135

judged. All statistical testing was done with SPSS version 23 (SPSS Inc., Chicago, IL, USA). p

The characteristics of the patient cohort included in the present study are shown in table 1. In short, the patients were 139

predominantly male (56%), middle-aged and obese. The sleep of these OSA patients demonstrated reduced sleep 140

efficiency (69.5%), an increased proportion of N1 sleep (13.1%) and a slightly reduced proportion of REM sleep (17.8%). 141

Their median AHI (16.7 events/h) suggested that moderate OSA was the predominant severity classification. 142

A total of 25557 hypopnea and 4779 obstructive apnea events were included into the analysis. The desaturation events 143

caused by obstructive apneas were statistically significantly (p≤0.004) longer, greater in area and deeper compared to 144

those related to hypopneas (figure 2, table 2). Adjusted mixed model analysis of all events showed that obstructive apneas 145

led to longer desaturation events (p

For decades, AHI has been used as the primary variable for estimating the severity of OSA [12]. Despite its common use, 166

AHI is acknowledged to have several limitations [11, 12, 21]. The main shortcoming of AHI is that it estimates the 167

severity of OSA by quantifying the rate at which respiratory events occur during sleep. Thus, the only information 168

exploited from the PSG is the frequency of these events. This may be suitable for patients with very few or no respiratory 169

events at all as well as for patients with vast number of respiratory events [21]. However, for patients with mild or 170

moderate OSA, this may not accurately estimate disease severity and predict its outcomes (e.g. cardiovascular, metabolic 171

and neurocognitive disorders) [11, 12, 22]. 172

One important aspect is the fact that AHI considers hypopneas and apneas as being of similar severity. Unfortunately, 173

there is limited information available whether or not apneas and hypopneas have the same biological, physiological and 174

health effects [12]. In the present study we estimated the differences between hypopneas and obstructive apneas by 175

comparing the desaturation severity related to these events. The analysis was adjusted for the confounding factors, gender, 176

sleep stage, sleeping position, age and BMI, which are known to influence the desaturation event characteristics [19]. The 177

desaturations related to obstructive apneas were statistically significantly deeper than the desaturations related to 178

hypopneas, which is in line with the previous findings [19]. In addition, the desaturations related to obstructive apneas 179

had statistically significantly larger areas and were statistically significantly longer than the desaturations related to 180

hypopneas. The findings further support the idea that the biological effects of obstructive apneas and hypopneas are not 181

equal. 182

Another shortcoming of AHI is the fact that all breathing cessation events are considered equal despite of the differences 183

in the durations of the events [11, 12], although there is known variation in the event durations between patients with 184

similar AHI [10]. In addition, there is some evidence that longer apneas are related to more severe desaturations compared 185

to shorter ones [16–18]. Our results revealed that the duration of the breathing cessation events is associated with the 186

severity of the related desaturations, which is in line with the previous findings showing increase in the depth of 187

desaturations with increasing breathing cessation event duration [19]. In the current study, desaturation duration, area and 188

depth were found to be statistically significantly correlated with the related hypopnea or obstructive apnea duration. The 189

severity of the desaturation events increased with increasing event duration. However, the increase in the depth of 190

desaturations caused by the increased duration of hypopneas was milder than that seen with the increasing duration of 191

obstructive apneas. In general the longer the events were the greater the difference was in the severity (area and depth) of 192

desaturation between events related to obstructive apneas and hypopneas. This indicates that especially longer obstructive 193

apneas could have more severe consequences than hypopneas with similar length. As the ventilation is disturbed but not 194

completely ceased during hypopneas, it is logical that the duration of the related desaturation increases while the 195

desaturation depth stabilizes and, on the contrary, lengthening of obstructive apneas further increase both the depth and 196

duration of related desaturation events. 197

In contrast to previous study by Peppard et al. [19], where desaturation depth was of interest, we also investigated the 198

durations and areas of desaturations besides the depth of desaturations. It can be assumed that desaturations with similar 199

depth but with 10 seconds duration and desaturations with 60 seconds duration have totally different consequences. In 200

the present study the depth of desaturation following hypopneas remained at a somewhat stable level of 4-5% while 201

increasing hypopnea duration increased the duration and area of the related desaturations. Analysing just the depth would 202

indicate that the severity of the desaturations would be almost equal, although the increased durations and areas show that 203

the severity is increasing with increasing hypopnea duration. Similarly the severity of the desaturations seems to increase 204

more rapidly as a function of obstructive apnea duration than the analysis based solely on the depth of desaturations would 205

indicate. Asano et al. [22] showed that in mild and moderate OSA patients integrated area of desaturations (IAD) is higher 206

in the patients with cardiovascular events compared to patients without cardiovascular events where as AHI showed no 207

differences between the groups. Therefore, more detailed analysis of the desaturation event characteristics, besides the 208

depth, could enhance the estimation of cardiovascular risk related to desaturation event severity. 209

Our study is not without limitations. In this study, we only explored obstructive apnea and hypopnea events that produced 210

SpO2 desaturations. It is evident that not all obstructive apneas and hypopneas induce desaturation. In the AASM2012 211

scoring guidelines there is no requirement for obstructive apneas to be followed by desaturation and hypopneas can be 212

followed by either desaturation or an arousal [5]. In the current study, the focus was on the desaturation event severity 213

related to breathing cessation event type and duration. As there was no information on the desaturation event 214

characteristics available related to hypopneas and obstructive apneas not followed by desaturation, they were excluded 215

from further analysis. Apneas not followed by desaturation and hypopneas connected to arousal most certainly contribute 216

to the overall severity of OSA and their significance in the severity estimation of the disease warrants further 217

investigations in the future. A further limitation in this study was that we could not control for pulmonary function, 218

although lung pathology can affect desaturation characteristics. Also central and mixed apneas were excluded from the 219

analyses and therefore the characteristics of desaturations related to central and mixed apneas need to be further 220

investigated. It is known that desaturations are a major cardiovascular risk factor in OSA [2, 15] and that integrated 221

desaturation area is linked to the risk of cardiovascular events [22]. However, it is acknowledged that clinical significance 222

of the differences found in the current study need further investigations. 223

All the current findings support the hypothesis that obstructive apneas and longer respiratory events in general induce 224

more severe desaturations. These more severe desaturations are a major factor in the cardiovascular risk related to OSA 225

[2, 15, 22]. It has been previously shown that more detailed analysis of the severity of respiratory and desaturation events 226

leads to more accurate estimation of cardiovascular risk related to OSA [13, 14, 22]. Our findings further support the idea 227

that more detailed analysis of the severity of the respiratory events is likely to enhance the estimation of the severity of 228

OSA and prediction of health-related outcomes. We propose that obstructive apnea events should be weighted with higher 229

factor than hypopneas and that the duration of the events should be considered when estimating the severity of OSA and 230

related cardiovascular risk. Most certainly both apnea and hypopnea events have important contributions to the severity 231

of OSA, but probably they should not be dealt equally when estimating the overall severity of OSA. 232

233

FUNDING 234

Financial support for this study was provided by the Tampere Tuberculosis, Emil Aaltonen, Olvi and Instrumentarium 235

Science Foundations, by the Research Foundation of the Pulmonary Diseases, by Seinäjoki Central Hospital (Grant 6020), 236

the Competitive State Research Financing of Expert Responsibility Area of Tampere University Hospital (Grants 237

VTR3114, VTR3221) and by the Department of Applied Physics, University of Eastern Finland. The sponsor had no role 238

in the design or conduct of this research. 239

240

CONFLICT OF INTEREST 241

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial 242

interest in the subject matter or materials discussed in this manuscript. 243

244

ETHICAL APPROVAL 245

The Institutional Human Research Ethics Committee of the Princess Alexandra Hospital approved this study 246

(HREC/16/QPAH/021). All procedures performed in studies involving human participants were in accordance with the 247

ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its 248

later amendments or comparable ethical standards. For this type of study formal consent by the patients was not required. 249

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Figure 1. Example of the duration (s), area (s%) and depth (%) of desaturation events following obstructive apnea and 312

hypopnea. The grey highlighting denotes the area (s%) of the desaturation events. au denotes arbitrary unis. 313

314

Obstructive apnea Hypopnea

Desaturation duration (s) Desaturation depth (%)

Desaturation area (s%)

315

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Figure 2. Median duration (A), area (B) and depth (C) of desaturations following obstructive apnea (circle) and hypopnea 319

(square) in different event duration classes. Desaturations following obstructive apneas are longer, have higher areas and 320

are deeper compared to desaturations following hypopneas. * Indicates statistically significantly different (p ≤ 0.004) 321

value between obstructive apnea and hypopnea, Mann-Whitney U test. Please note reverse y-axis in panel (C). 322

323

B)

C)

A)

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Table 1. Patient characteristics. 325 Parameter Total number of patients (females) 395 (175) Age (y) 56.0 (45.0-66.0) BMI (kg/m2) 33.3 (28.7-39.3) Co-morbidities, % of patients Hypertension Hyperlipidemia Type 2 diabetes GERD Depression Ischemic heart disease COPD

44.1 11.6 24.6 25.3 23.0 14.4 11.1

TST (min) 304.0 (249.5-362.5) Sleep Efficiency (%) 69.5 (55.9-80.5) Sleep Stage Proportion (% of TST) NREM Total (%) 82.1 (77.7-87.6) N1 (%) 13.1 (7.4-20.9) N2 (%) 49.2 (42.4-57.0) N3 (%) 14.7 (6.3-24.4) REM (%) 17.8 (12.4-22.3) AHI (Events/h) 16.7 (8.2-34.1) AI (Events/h) 1.1 (0.2-4.5) HI (Events/h) 14.2 (6.9-27.0)

Values are presented as median (inter-quartile range). BMI; body mass index, GERD; gastroesophageal reflux disease, 326 COPD; chronic obstructive pulmonary disease, TST; total sleep time, NREM; non-REM sleep, N1; stage 1 sleep, N2; 327 stage 2 sleep, N3; stage 3 sleep, AHI; apnea-hypopnea index, AI; apnea index, HI; hypopnea index. 328

Table 2. The median (inter-quartile range) duration, depth, and area of desaturation events related to obstructive apnea or hypopnea events in different durational categories (n=395). 329 Obstructive apneas are related to more severe desaturation than hypopneas in all durational categories. The severity of desaturation increases with increasing length of both 330 hypopneas and obstructive apneas. The left column describes the durational category inside which the included obstructive apnea and hypopnea events are in. 331

Duration (s) Ap (n) Hyp (n) DesApDu (s) DesHypDu (s) DesApA (s%) DesHypA (s%) DesApDe (%) DesHypDe (%)

10 to ≤15 674 5705 23.1 22.0# 96.5 52.1# 8.0 4.0#

(19.0-28.0)* (16.1-29.0)* (52.9-158.3)* (33.7-84.2)* (5.0-12.0) (3.0-6.0)*

15 to ≤20 952 6259 27.1 25.9# 109.9 64.3# 8.0 4.0#

(22.0-34.0)* (20.0-33.0)* (67.0-197.1)* (41.6-105.0)* (5.0-12.0)* (3.0-6.0)*

20 to ≤25 891 4651 33.0 29.1# 168.6 76.6# 10.0 5.0#

(27.0-39.0)* (23.1-37.0)* (90.3-310.9)* (48.6-125.7)* (6.0-16.0) (3.0-7.0)*

25 to ≤30 711 2991 38.0 34.0# 195.1 91.8# 10.0 5.0#

(31.0-44.1)* (27.1-41.0)* (104.4-370.7)* (57.9-152.2)* (6.0-18.0)* (3.0-7.0)*

30 to ≤35 538 1970 41.1 38.0# 236.5 106.8# 12.0 5.0#

(36.0-48.0)* (31.4-45.0)* (147.9-456.4)* (68.3-175.8)* (8.0-20.0)* (4.0-8.0)

35 to ≤40 416 1265 48.0 43.1# 298.4 121.4# 13.0 5.0#

(40.0-54.0)* (34.1-50.0)* (164.5-620.6) (73.9-209.9) (8.0-25.0) (4.0-8.0)

40 to ≤45 264 912 54.0 46.5# 359.0 125.2# 13.0 5.0#

(45.0-59.0) (38.2-54.0)* (189.8-723.7)* (80.6-225.3) (8.0-26.0) (4.0-8.0)

>45 333 1804 60.0 56.8# 409.9 162.1# 14.0 5.0#

(48.1-72.0) (43.1-70.0) (181.5-804.6) (94.9-285.8.0) (7.0-26.0) (4.0-8.0)

All 4779 25557 35.0 30.0# 173.9 76.4# 10.0 5.0#

(25.5-46.0) (21.4-41.0) (88.5-344.1) (46.0-135.1) (6.0-17.0) (3.0-7.0) Notations: Ap: obstructive apnea, Hyp: hypopnea, DesApDu: desaturation event duration related to obstructive apnea event, DesHypDu: desaturation evet duration related to 332 hypopnea, DesApA: area of desaturation event related to obstructive apnea, DesHypA: area of desaturation event related to hypopnea, DesApDe: depth of desaturation event related 333 to obstructive apnea, DesHypDe: depth of desaturation related to hypopnea. #Statistically significantly different (p ≤ 0.004) than the corresponding value of desaturation related to 334 obstructive apnea, Mann-Whitney U test. *Statistically significantly different (p < 0.05) than value in one level longer durational category, Kruskal-Wallis pairwise comparison. 335 336 337