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Pulse transit time changes in subjects exhibiting sleep disordered breathing
Respiratory Medicine 122 (2017) 18e22
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Pulse transit time changes in subjects exhibiting sleep disordered breathing Biswajit Chakrabarti a, *, Stephen Emegbo b, Sonya Craig a, Nick Duffy a, John O'Reilly a a b
Aintree Chest Centre, University Hospital Aintree, Liverpool, United Kingdom Liverpool Sleep and Ventilation Centre, University Hospital Aintree, Liverpool, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 October 2016 Received in revised form 19 November 2016 Accepted 19 November 2016 Available online 21 November 2016
Introduction: Pulse Transit Time (PTT) represents a non-invasive marker of sleep fragmentation in OSAS. Little is known regarding PTT in sleepy subjects exhibiting nocturnal Inspiratory Flow Limitation (IFL) in the absence of apneas or desaturation. Materials and methods: The IFL cohort was gender and age matched to subjects with OSAS and a cohort where Sleep Disordered Breathing (SBD)/IFL was absent (“Non Flow Limited” or NFL cohort); PTT Arousal index (PTT Ar) defined by number of PTT arousals per hour. Results: 20 subjects meeting criteria for the IFL cohort were aged and gender matched with OSAS and “NFL” subjects. Females comprised 65% of the IFL cohort; the mean BMI of the IFL cohort was significantly higher than the NFL cohort (34.25 v 28.90; p ¼ 0.016) but not when compared to the OSAS cohort (34.25 v 36.31; p ¼ 0.30). The PTT Ar in the IFL cohort (33.67 h) was significantly higher than the NFL cohort (23.89 h) but significantly lower than the OSAS cohort (55.21 h; F ¼ 8.76; p < 0.001). PTT Ar was found to positively correlate with AHI (CC ¼ 0.46; p < 0.001), ODI (CC ¼ 0.47; p < 0.001) and RDI (CC ¼ 0.49; p < 0.001). Within the IFL cohort, PTT Ar positively correlated with age (CC ¼ 0.501; p ¼ 0.024) but not gender and BMI. Conclusion: The PTT Arousal Index increased proportionately with severity of SDB with significantly higher markers of arousal in sleepy subjects exhibiting nocturnal IFL when compared to controls. Subjects exhibiting IFL were predominantly female with an elevated BMI. IFL may thus represent a significant pathogenic entity in the development of daytime sleepiness. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Sleep apnoea Pulse transit time Flow limitation Snoring
1. Introduction The diagnosis of Obstructive Sleep Apnoea Syndrome (OSAS) in an individual has been traditionally based on the finding of an elevated Apnoea-Hypopnoea Index (AHI) [1] A cohort of patients presenting with excessive daytime sleepiness (EDS) have been reported to exhibit Respiratory Effort Related Arousals (RERAs) in the absence of apnoeas on Polysomnography (PSG) preceded by a progressively negative intra-thoracic pleural pressure thus denoting arousal due to increasing efforts to maintain a patent airway [2]. As a result, the International Classification of Sleep Disorders now includes RERAs within the definition of hypopnoeas [3]. In relation to this, the occurrence of flow limited breathing during sleep albeit in the absence of apnoea has also been increasingly recognised in
* Corresponding author. E-mail address: [email protected] (B. Chakrabarti). http://dx.doi.org/10.1016/j.rmed.2016.11.014 0954-6111/© 2016 Elsevier Ltd. All rights reserved.
the literature [4,5]. Furthermore, the application of certain criteria to Inspiratory Flow Limitation (IFL) when detected using a Nasal Cannula pressure transducer has been demonstrated to act as a surrogate for RERAs on PSG [6]. This suggests that, in an individual complaining of EDS, the presence of significant nocturnal flow limitation in a sleep study may not necessarily represent a benign occurrence and may warrant further investigation. This finding becomes increasingly relevant in an era where ‘Out of Centre’ or “Home Sleep Testing” is gaining increasingly popularity in favour over in-patient PSG as clinicians in these settings may not take the presence and degree of Flow Limitation into consideration. PTT (Pulse Transit Time) represents a non-invasive indirect marker of sleep fragmentation in subjects with OSA reflecting the autonomic imbalances associated with sleep-disordered breathing (SDB) [7]. PTT refers to the time taken for the arterial pulse pressure wave to travel from between 2 separate sites, usually the aortic valve to a peripheral site such as the finger. In OSA, obstruction of the upper airway results in a fall in blood pressure. The consequent
B. Chakrabarti et al. / Respiratory Medicine 122 (2017) 18e22
reduction in vascular tone is associated with a longer time for the Pulse wave to reach the periphery, and results in an “increment” in the PTT [8]. The effect of such airway obstruction is an arousal from sleep and the resumption of a patent upper airway, accompanied by an increase in blood pressure, stiffening of the arterial wall and increase in vascular tone leading to a ”decrement” in the PTT [9]. Changes in PTT have been demonstrated to correlate with changes in oxygen saturation, oesophageal pressure swings, inspiratory effort and EEG arousals in the setting of OSA and have also been shown to be useful in detecting obstructive non-apnoeic respiratory events [10,11]. Little is known comparing PTT indices in persons with OSAS with those who present with excessive daytime sleepiness (EDS) in whom sleep studies exhibit IFL in the absence of apneas or associated desaturation. The latter represent a group that may be overlooked if healthcare professionals use “Home Sleep Testing” in isolation to diagnose the presence of SBD, a practice common in many healthcare settings. Furthermore, PTT indices can readily be determined using Home Sleep Testing. In this observational hypothesis generating study, we aimed to determine whether PTT indices in subjects with excessive daytime sleepiness and IFL during sleep differ from those with a diagnosis of OSAS, and from an additional cohort exhibiting no evidence of IFL or any other sleep disordered breathing. 2. Materials and methods Adult patients (aged > 18 years) were recruited from new referrals to the Liverpool Sleep and Ventilation Centre at University Hospital Aintree between October 2007 and November 2013. Sleep studies were performed using an ambulatory polygraphic device (SOMNOScreen Plus™,SOMNOmedics GmbH, Randersacker, D97236, Germany). The polygraph recorded pulse oximetry, electrocardiograph (ECG), thoracic and abdominal motion by inductive plethysmography, body position, oronasal pressure, bipolar channel limb movements (anterior tibialis) and ambient light levels. Electrodes and sensors were directly attached to patients by an experienced sleep physiologist with data acquisition preprogrammed to commence 30 min before reported bedtime with maximal recording time of 12 h. Patients returned the device to the sleep laboratory the following morning, with recordings downloaded and computer pre-processed (DOMINO™ Software, ver. 2.6.0, SOMNOmedics GmbH, Randersacker, D-97236, Germany). The polygraph was then subject to manual assessment by an experienced clinical physiologist trained in accordance with American Academy of Sleep Medicine (AASM) criteria [12]. Flow limited breaths were measured using a nasal pressure transducer. Where the nasal pressure transducer signal was compromised, the sum of respiratory inductive plethysmography (RIP) effort was then used as a surrogate measure of flow changes. All Sleep studies were manually inspected by a Senior Sleep Physiologist (SE). Apnoeas and hypopneas were scored manually according to AASM criteria. A “flow limited” event was scored (always by visual inspection) based on previous criteria, as a separate entity and not contiguous with the AHI, as 2 consecutive breaths, lasting a minimum of 10 s and exhibiting a flattened or “non-sinusoidal” appearance, yet with fall in peak amplitude not meeting the 30% requirement for hypopnoea, and with an abrupt ending returning to breaths with a sinusoidal shape, and with absence of oxygen desaturation [6]. The Respiratory Disturbance Index (RDI) represented the sum of the AHI and the “Flow Limitation” Index. The PTT was calculated automatically using the manufacturers analysis software and was defined as the interval between the electrocardiographic R wave and the point corresponding to 50% of the height of the ascending pulse waveform (detected by a
19
plethysmographic finger probe). The ECG and pulse wave signal were sampled at 512 Hz, with ECG and pulse signals from periods of assumed sleep included in the analysis., with sleep defined by a consolidated fall in Heart Rate, when in a recumbent body position and the absence of generalised body movement (actigraphy). The PTT was continuously monitored and the average PTT time for the cohorts reported [7]. PTT arousals were automatically derived from the raw PTT signal; a PTT arousal or “deceleration” was defined as a decline in the PTT signal of 15 ms, lasting 5 s [9]. The PTT deceleration or “Arousal” index was defined as the number of PTT arousals i.e. decelerations per hour of TST (“Arousal” Index: PTT Ar). A PTT increase was defined as an increase in the average signal of 15 ms, lasting at least 5 s, with the PTT incremental index (PTT Inc) defined as the number of PTT increases per hour of TST. An IFL cohort was selected on the basis of a history of excessive sleepiness and nocturnal snoring associated with an AHI <5/hr and RDI at least double that of the AHI. The IFL cohort was gender and age matched (±2yrs of age at time of study) to 2 additional cohorts: i) patients with EDS, nocturnal snoring and AHI S 15/hr (“OSAS” cohort) ii) those referred to the Sleep service in whom cardiorespiratory polygraphy had demonstrated the absence of significant SDB, i.e. both AHI and RDI <5/hr (“Non Flow Limited” or NFL cohort). All subjects in the IFL and OSAS cohorts presented with Excessive Daytime Sleepiness (EDS) defined by an Epworth Sleepiness Score (ESS)>¼10) or an appropriate level of tiredness experienced by the subject resulting in functional impairment deemed significant by a Consultant Sleep Physician and presence of Snoring disruptive to partner. Subjects with hypoventilation from the baseline diagnostic investigation (greater than 20 min spent below 90%) or with any suspected or proven secondary sleep pathology e.g. Periodic Limb Movement, Parasomnia, Narcolepsy, Circadian Disorder were specifically excluded from the study as well as those with technically compromised polysomnograms (including those where percentage failure of flow signal was 20% or greater) and where Time In Bed (TIB) was <7 h or >9 h. The study received formal approval by the Clinical Lead for sleep and Institutional Review Board of our hospital. 3. Statistical analysis Statistical analysis was performed using SPSS 20.0 (IBM Corp Rel 2011; IBM SPSS Statistics for Windows V 20 Armock NY). Data are presented as group mean and with standard deviations. A 3-way ANOVA was used to evaluate between-group interactions, with alpha set at 0.05. A 2 way ANOVA was used to evaluate the difference between 2 groups. A Pearson's Correlation coefficient was also used to delineate the nature of PTT changes with variables underlying sleep disordered breathing and other key demographics. Statistical significance was defined as a p value < 0.05. 4. Results 20 subjects (AHI 3.84 (SD 1.16)), identified as meeting criteria for inclusion in the IFL cohort, were aged and gender matched with 20 subjects meeting criteria for OSAS (AHI 49.93 (SD 16.77)) as well as 20 subjects with no evidence of significant sleep disordered breathing (“NFL” cohort; AHI 1.01 (SD 1.05)). Table 1 outlines key demographics in the IFL, OSAS and NFL subjects. Of the 20 subjects in the NFL cohort, 14 presented with “simple snoring” in the absence of EDS, 2 presented with insomnia, 2 with nightmares, 1 with parasomnia and 1 with generalised fatigue. 13 subjects (65%) in the IFL cohort were female. The mean BMI of the IFL cohort was significantly higher than the NFL cohort (ANOVA 34.25 (6.63) v 28.90 (6.61); 95%CI 1.06e9.67; F ¼ 6.36 p ¼ 0.016). The mean BMI of the IFL cohort was not found to differ significantly
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Table 1 Key demographics in the IFL, OSAS and NFL “Control” cohorts.
Age (years) BMI (kg/m2) AHI (per hour) RDI (per hour) ODI(per hour) Mean Oxygen Saturation Snore Index PTT Arousal/Deceleration Index (PTT Ar) PTT Incremental Index (PTT IncI) Epworth Sleepiness Score (ESS) at presentation Presence of Hypertension Presence of Cardiac Disease
Inspiratory Flow Limitation (IFL) Cohort (n ¼ 20; female ¼ 13)
Obstructive Sleep Apnoea Syndrome (OSAS) Cohort (n ¼ 20); female ¼ 13
“NFL” Control Group (n ¼ 20; female ¼ 13)
F Value
P value
47 (8.39) 34.25 (6.63) 3.84 (1.16) 17.71 (5.34) 4.49 (2.37) 95.05 (1.85) 210.73 (173.11) 33.67 (23.34) 34.56 (24.27) 16.35 (3.65) 5/20 1/20
45 (8.30) 36.31 (5.62) 48.93(16.77) 57.56 (16.00) 40.42 (15.52) 93.75 (1.55) 305.76 (175.54) 55.21 (29.30) 56.59 (31.00) 14.45 (5.52) 5/20 1/20
47 (8.79) 28.90 (6.81) 1.01 (1.05) 2.63 (1.34) 1.18 (1.47) 95.90 (1.48) 73.39 (66.74) 23.89 (18.88) 25.30 (18.34) 7.90 (6.21) 0/20 0/20
F ¼ 0.28 F ¼ 7.21 F ¼ 152.78 F ¼ 159.72 F ¼ 114.21 F ¼ 10.14 F ¼ 12.55 8.76 8.19 F ¼ 12.49 F ¼ 3.16 F ¼ 0.5
P P P P P P P P P P P P
from the OSAS cohort (ANOVA; 34.25 (6.63) v 36.31 (5.62); 95% CI -5.99e1.88; F ¼ 1.12 p ¼ 0.30). When combining the OSAS, IFL and NFL cohorts, a significant correlation was noted between the PTT Ar and PTT Inc (CC ¼ 0.993; p < 0.001). The PTT Ar in the IFL cohort (33.67±(23.34)/hr) was significantly higher than that measured in the NFL cohort (23.89 ±(18.88)/hr) denoting a higher degree of cardiovascular arousal in the IFL cohort. The greatest level of cardiovascular arousal was noted in the OSAS cohort who exhibited the highest PTT Ar (55.21± (29.30)/hr; 3-way ANOVA; F ¼ 8.76; p < 0.001; see Fig. 1). The PTT Ar was also found to correlate significantly with the AHI (CC ¼ 0.46; p < 0.001) and the ODI (CC ¼ 0.47; p < 0.001) of the study population. A statistically significant correlation was also observed between PTT Ar and the RDI of the study population (CC ¼ 0.49; p < 0.001) suggesting that the extent of cardiovascular increased with the degree of sleep-disordered breathing when encompassing hypopnoeas accompanied by desaturation, apneas as well as flow limited breaths resulting in RERAs (see Fig. 2; R2 ¼ 0.24). A non-significant trend in correlation was observed between
¼ 0.76 ¼ 0.002 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 ¼ 0.001 < 0.001 ¼ 0.05 ¼ 0.61
PTT Ar and age (CC ¼ 0.29; p ¼ 0.07). No significant correlation was reported between PTT Ar with BMI (CC ¼ 0.16; p ¼ 0.22) or Epworth Score (CC ¼ 0.03; p ¼ 0.84). 5. Discussion The presence of nocturnal inspiratory flow limitation without associated oxygen desaturation is a finding which may be overlooked by clinicians who use Home Sleep Testing to rule in or out the diagnosis of OSAS. Our study has shown that the PTT Arousal Index was greater in adult subjects presenting with EDS and exhibiting nocturnal IFL in comparison to a group exhibiting no evidence of SDB. This supports the hypothesis that the presence of nocturnal IFL represents a potentially significant pathogenic entity in the development of daytime sleepiness. Furthermore, we propose that the demographics reported in our IFL cohort raises potential gender differences in the pathophysiology of SBD. Females constituted 65% of the IFL cohort in contrast to the literature in OSAS where traditionally, a male predominance is described [13]. We reported that the BMI of the IFL cohort (mean BMI of 34.25 kg/
Fig. 1. Relationship between PTT arousal (Deceleration) index and sleep disordered breathing (by category: IFL, OSAS and NFL cohort).
B. Chakrabarti et al. / Respiratory Medicine 122 (2017) 18e22
21
Fig. 2. The relationship between PTT arousal (Deceleration) index and RDI.
m2) did not differ significantly from the OSAS cohort. This suggests that a subset of obese predominantly female individuals may present with EDS related to IFL rather than exhibiting apnoeas or hypopneas associated with desaturation. Detailed studies are needed to gain a better understanding of the mechanism by which females may have a propensity to develop IFL resulting in daytime sleepiness. Such studies should include quantification of visceral fat distribution in IFL subjects, particularly in relation to gender. Interestingly, our study also reported a higher ESS in the IFL cohort when compared to the OSAS subjects. Whilst this may be explained by the fact that the IFL cohort was a selected population of matched subjects specifically referred with EDS, further studies are required to better understand key clinical and physiological differences between the IFL and OSAS cohorts. The highest PTT Arousal Indices were seen in the OSAS cohort exhibiting a mean Arousal Index greater than 55 events/hour. A study of paediatric subjects with OSAS, Upper Airways Resistance Syndrome (UARS), primary snorers and healthy subjects reported that the PTT Ar did not significantly differ between the OSAS and UARS groups, but was significantly lower in primary snorers and “healthy normals” [14]. However, this study included only subjects with a mild degree of OSAS with a mean AHI 10.6 compared to 48.9 events/hour in our OSAS cohort this potentially accounting for the greater difference in PTT Ar reported in our study. A study of 144 subjects with OSA revealed that the correlation between the PTT Arousal index and AHI was 0.44, a value similar to our OSA cohort [15]. Our study found that the PTT Arousal index was also found to correlate with the RDI, an index encompassing the degree of IFL. A study of OSAS patients randomised to CPAP aiming either to suppress IFL as well as apnoeas and hypopneas or to abolish only apnoeas and hypopneas reported a greater scatter in Maintenance of Wakefulness Test values and decreased CPAP usage in the latter group [16]. Further studies are required to determine whether CPAP therapy aiming primarily to reduce the PTT Arousal Index through abolishing flow limitation as opposed to reducing AHI alone might lead to superior clinical outcomes. A limitation of our study is in the utilisation of cardio-
respiratory polygraphy rather than PSG. However, in our study, all polygraphs were manually interpreted by a senior sleep physiologist using direct visual analysis and this has been demonstrated to be more aligned to a “polysomnographic” AHI when compared to automated analysis [17]. Furthermore, we used specific set criteria to define a “flow limited” event demonstrated to correspond to RERAs on PSG as demonstrated by Ayappa et al. [6]. Nonetheless, it is important to stress that the findings of our study apply only to subjects with IFL diagnosed under specific criteria along with presenting with EDS and this cannot be extrapolated to subjects presenting with IFL but with the absence of daytime impairment. It is also important to consider the limitations of interpreting PTT in clinical practice. For example, PTT indices may be affected by sleep fragmentation due to external stimuli or non-respiratory events, the occurrence of artefact (interference with the photoplethysmographic signal at the finger and disruption of ECG leads affected by chest wall movement) and during the presence of marked respiratory variation particularly during REM sleep [8]. This may be a factor contributing to the elevated PTT Arousal Index in the “NFL” subjects exhibiting no evidence of SDB.
6. Conclusion In summary, this study demonstrates that the PTT Arousal Index, a marker of sleep fragmentation, was found to be significantly higher in a group of subjects presenting with EDS exhibiting inspiratory flow limitation in comparison to subjects exhibiting an absence of sleep disordered breathing supporting the concept that the occurrence of nocturnal flow limited breathing may represent a relevant mechanism in the pathogenesis of daytime sleepiness.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Contributorship BC, SC, ND and JFOR conceived and designed the research. BC, SE and JFOR acquired, analysed and interpreted the data. BC drafted the manuscript and BC, SC, ND and JFOR revised it critically for important intellectual content. Competing interests Nil. References [1] J.R. Stradling, R.J.O. Davies, Sleep. 1: obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history, Thorax 59 (1) (2004) 73e78. [2] C. Guilleminault, R. Stoohs, A. Clerk, J. Simmons, M. Labanowski, From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness, Sleep 15 (6 Suppl) (1992) S13eS16. [3] American Academy of Sleep Medicine, International Classification of Sleep Disorders, third ed., American Academy of Sleep Medicine, Darien, IL, 2014. [4] G. Calero, R. Farre, E. Ballester, L. Hernandez, N. Daniel, J.M. Montserrat Canal, Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome, Respir. Med. 100 (5) (2006) 813e817. [5] L.O. Palombini, S. Tufik, D.M. Rapoport, Ia Ayappa, C. Guilleminault, L.B.M. de Godoy, L.S. Castro, L. Bittencourt, Inspiratory flow limitation in a normal ~o Paulo, Brazil, Sleep 36 (11) (2013) 1663e1668. population of adults in Sa [6] I. Ayappa, R.G. Norman, A.C. Krieger, A. Rosen, R.L. O’malley, D.M. Rapoport, Non-Invasive detection of respiratory effort-related arousals (RERAs) by a nasal cannula/pressure transducer system, Sleep 23 (6) (2000) 763e771.
[7] D.J. Pitson, J.R. Stradling, Value of beat-to-beat blood pressure changes, detected by pulse transit time, in the management of the obstructive sleep apnoea/hypopnoea syndrome, Eur. Respir. J. 12 (3) (1998) 685e692. pin, P. Le vy, A.Pulse transit time: an appraisal of [8] R.P. Smith, J. Argod, J.-L. Pe potential clinical applications, Thorax 54 (1999) 452e457. [9] D.J. Pitson, A. Sandell, R. Van Den Hout, et al., Use of pulse transit time as a measure of inspiratory effort in patients with obstructive sleep apnoea, Eur. Respir. J. 8 (10) (1995) 1669e1674. [10] D.J. Pitson, J.R. Stradling, Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnoea, their relationship to EEG arousals, respiratory events and subjective sleepiness, J. Sleep. Res. 7 (1) (1998) 53e59. [11] J. Argod, J.-L. Pepin, P. Levy, Differentiating Obstructive and Central Sleep Respiratory Events Using Pulse Transit Time (PTT), 158, AJRCCM, 1998, pp. 1778e1783. [12] R.B. Berry, R. Budhiraja, D.J. Gottlieb, D. Gozal, C. Iber, V.K. Kapur, C.L. Marcus, R. Mehra, S. Parthasarathy, S. Quan, S. Redline, K. Strohl, S.L.D. Ward, M.M. Tangredi, Rules for scoring respiratory events in sleep: update of the 2007 AASM manual for the scoring of sleep and associated events, J. Clin. Sleep. Med. 8 (5) (2012) 597e619. [13] T. Young, M. Palta, J. Dempsey, J. Skatrud, The occurrence of sleep-disordered breathing among middle-aged adults, N. Engl. J. Med. (1993) 1230e1235. [14] E.S. Katz, J. Lutz, C. Black, C.L. Marcus, Pulse transit time as a measure of arousal and respiratory effort in children with sleep-disordered breathing, Pediatr. Res. [Internet] 53 (4) (2003) 580e588. [15] D.J. Schwartz, The pulse transit time arousal index in obstructive sleep apnea before and after CPAP, Sleep. Med. 6 (3) (2005) 199e203. [16] J.C. Meurice, J. Paquereau, A. Denjean, F. Patte, F. Series, Influence of correction of flow limitation on continuous positive airway pressure efficiency in sleep apnoea/hypopnoea syndrome, Eur. Respir. J. 11 (5) (1998) 1121e1127. [17] J.M. Calleja, S. Esnaola, R. Rubio, J. Duran, Comparison of a cardiorespiratory device versus polysomnography for diagnosis of sleep apnoea, Eur. Respir. J. 20 (6) (2002) 1505e1510.
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Pulse transit time changes in subjects exhibiting sleep disordered breathing Biswajit Chakrabarti a, *, Stephen Emegbo b, Sonya Craig a, Nick Duffy a, John O'Reilly a a b
Aintree Chest Centre, University Hospital Aintree, Liverpool, United Kingdom Liverpool Sleep and Ventilation Centre, University Hospital Aintree, Liverpool, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 October 2016 Received in revised form 19 November 2016 Accepted 19 November 2016 Available online 21 November 2016
Introduction: Pulse Transit Time (PTT) represents a non-invasive marker of sleep fragmentation in OSAS. Little is known regarding PTT in sleepy subjects exhibiting nocturnal Inspiratory Flow Limitation (IFL) in the absence of apneas or desaturation. Materials and methods: The IFL cohort was gender and age matched to subjects with OSAS and a cohort where Sleep Disordered Breathing (SBD)/IFL was absent (“Non Flow Limited” or NFL cohort); PTT Arousal index (PTT Ar) defined by number of PTT arousals per hour. Results: 20 subjects meeting criteria for the IFL cohort were aged and gender matched with OSAS and “NFL” subjects. Females comprised 65% of the IFL cohort; the mean BMI of the IFL cohort was significantly higher than the NFL cohort (34.25 v 28.90; p ¼ 0.016) but not when compared to the OSAS cohort (34.25 v 36.31; p ¼ 0.30). The PTT Ar in the IFL cohort (33.67 h) was significantly higher than the NFL cohort (23.89 h) but significantly lower than the OSAS cohort (55.21 h; F ¼ 8.76; p < 0.001). PTT Ar was found to positively correlate with AHI (CC ¼ 0.46; p < 0.001), ODI (CC ¼ 0.47; p < 0.001) and RDI (CC ¼ 0.49; p < 0.001). Within the IFL cohort, PTT Ar positively correlated with age (CC ¼ 0.501; p ¼ 0.024) but not gender and BMI. Conclusion: The PTT Arousal Index increased proportionately with severity of SDB with significantly higher markers of arousal in sleepy subjects exhibiting nocturnal IFL when compared to controls. Subjects exhibiting IFL were predominantly female with an elevated BMI. IFL may thus represent a significant pathogenic entity in the development of daytime sleepiness. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Sleep apnoea Pulse transit time Flow limitation Snoring
1. Introduction The diagnosis of Obstructive Sleep Apnoea Syndrome (OSAS) in an individual has been traditionally based on the finding of an elevated Apnoea-Hypopnoea Index (AHI) [1] A cohort of patients presenting with excessive daytime sleepiness (EDS) have been reported to exhibit Respiratory Effort Related Arousals (RERAs) in the absence of apnoeas on Polysomnography (PSG) preceded by a progressively negative intra-thoracic pleural pressure thus denoting arousal due to increasing efforts to maintain a patent airway [2]. As a result, the International Classification of Sleep Disorders now includes RERAs within the definition of hypopnoeas [3]. In relation to this, the occurrence of flow limited breathing during sleep albeit in the absence of apnoea has also been increasingly recognised in
* Corresponding author. E-mail address: [email protected] (B. Chakrabarti). http://dx.doi.org/10.1016/j.rmed.2016.11.014 0954-6111/© 2016 Elsevier Ltd. All rights reserved.
the literature [4,5]. Furthermore, the application of certain criteria to Inspiratory Flow Limitation (IFL) when detected using a Nasal Cannula pressure transducer has been demonstrated to act as a surrogate for RERAs on PSG [6]. This suggests that, in an individual complaining of EDS, the presence of significant nocturnal flow limitation in a sleep study may not necessarily represent a benign occurrence and may warrant further investigation. This finding becomes increasingly relevant in an era where ‘Out of Centre’ or “Home Sleep Testing” is gaining increasingly popularity in favour over in-patient PSG as clinicians in these settings may not take the presence and degree of Flow Limitation into consideration. PTT (Pulse Transit Time) represents a non-invasive indirect marker of sleep fragmentation in subjects with OSA reflecting the autonomic imbalances associated with sleep-disordered breathing (SDB) [7]. PTT refers to the time taken for the arterial pulse pressure wave to travel from between 2 separate sites, usually the aortic valve to a peripheral site such as the finger. In OSA, obstruction of the upper airway results in a fall in blood pressure. The consequent
B. Chakrabarti et al. / Respiratory Medicine 122 (2017) 18e22
reduction in vascular tone is associated with a longer time for the Pulse wave to reach the periphery, and results in an “increment” in the PTT [8]. The effect of such airway obstruction is an arousal from sleep and the resumption of a patent upper airway, accompanied by an increase in blood pressure, stiffening of the arterial wall and increase in vascular tone leading to a ”decrement” in the PTT [9]. Changes in PTT have been demonstrated to correlate with changes in oxygen saturation, oesophageal pressure swings, inspiratory effort and EEG arousals in the setting of OSA and have also been shown to be useful in detecting obstructive non-apnoeic respiratory events [10,11]. Little is known comparing PTT indices in persons with OSAS with those who present with excessive daytime sleepiness (EDS) in whom sleep studies exhibit IFL in the absence of apneas or associated desaturation. The latter represent a group that may be overlooked if healthcare professionals use “Home Sleep Testing” in isolation to diagnose the presence of SBD, a practice common in many healthcare settings. Furthermore, PTT indices can readily be determined using Home Sleep Testing. In this observational hypothesis generating study, we aimed to determine whether PTT indices in subjects with excessive daytime sleepiness and IFL during sleep differ from those with a diagnosis of OSAS, and from an additional cohort exhibiting no evidence of IFL or any other sleep disordered breathing. 2. Materials and methods Adult patients (aged > 18 years) were recruited from new referrals to the Liverpool Sleep and Ventilation Centre at University Hospital Aintree between October 2007 and November 2013. Sleep studies were performed using an ambulatory polygraphic device (SOMNOScreen Plus™,SOMNOmedics GmbH, Randersacker, D97236, Germany). The polygraph recorded pulse oximetry, electrocardiograph (ECG), thoracic and abdominal motion by inductive plethysmography, body position, oronasal pressure, bipolar channel limb movements (anterior tibialis) and ambient light levels. Electrodes and sensors were directly attached to patients by an experienced sleep physiologist with data acquisition preprogrammed to commence 30 min before reported bedtime with maximal recording time of 12 h. Patients returned the device to the sleep laboratory the following morning, with recordings downloaded and computer pre-processed (DOMINO™ Software, ver. 2.6.0, SOMNOmedics GmbH, Randersacker, D-97236, Germany). The polygraph was then subject to manual assessment by an experienced clinical physiologist trained in accordance with American Academy of Sleep Medicine (AASM) criteria [12]. Flow limited breaths were measured using a nasal pressure transducer. Where the nasal pressure transducer signal was compromised, the sum of respiratory inductive plethysmography (RIP) effort was then used as a surrogate measure of flow changes. All Sleep studies were manually inspected by a Senior Sleep Physiologist (SE). Apnoeas and hypopneas were scored manually according to AASM criteria. A “flow limited” event was scored (always by visual inspection) based on previous criteria, as a separate entity and not contiguous with the AHI, as 2 consecutive breaths, lasting a minimum of 10 s and exhibiting a flattened or “non-sinusoidal” appearance, yet with fall in peak amplitude not meeting the 30% requirement for hypopnoea, and with an abrupt ending returning to breaths with a sinusoidal shape, and with absence of oxygen desaturation [6]. The Respiratory Disturbance Index (RDI) represented the sum of the AHI and the “Flow Limitation” Index. The PTT was calculated automatically using the manufacturers analysis software and was defined as the interval between the electrocardiographic R wave and the point corresponding to 50% of the height of the ascending pulse waveform (detected by a
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plethysmographic finger probe). The ECG and pulse wave signal were sampled at 512 Hz, with ECG and pulse signals from periods of assumed sleep included in the analysis., with sleep defined by a consolidated fall in Heart Rate, when in a recumbent body position and the absence of generalised body movement (actigraphy). The PTT was continuously monitored and the average PTT time for the cohorts reported [7]. PTT arousals were automatically derived from the raw PTT signal; a PTT arousal or “deceleration” was defined as a decline in the PTT signal of 15 ms, lasting 5 s [9]. The PTT deceleration or “Arousal” index was defined as the number of PTT arousals i.e. decelerations per hour of TST (“Arousal” Index: PTT Ar). A PTT increase was defined as an increase in the average signal of 15 ms, lasting at least 5 s, with the PTT incremental index (PTT Inc) defined as the number of PTT increases per hour of TST. An IFL cohort was selected on the basis of a history of excessive sleepiness and nocturnal snoring associated with an AHI <5/hr and RDI at least double that of the AHI. The IFL cohort was gender and age matched (±2yrs of age at time of study) to 2 additional cohorts: i) patients with EDS, nocturnal snoring and AHI S 15/hr (“OSAS” cohort) ii) those referred to the Sleep service in whom cardiorespiratory polygraphy had demonstrated the absence of significant SDB, i.e. both AHI and RDI <5/hr (“Non Flow Limited” or NFL cohort). All subjects in the IFL and OSAS cohorts presented with Excessive Daytime Sleepiness (EDS) defined by an Epworth Sleepiness Score (ESS)>¼10) or an appropriate level of tiredness experienced by the subject resulting in functional impairment deemed significant by a Consultant Sleep Physician and presence of Snoring disruptive to partner. Subjects with hypoventilation from the baseline diagnostic investigation (greater than 20 min spent below 90%) or with any suspected or proven secondary sleep pathology e.g. Periodic Limb Movement, Parasomnia, Narcolepsy, Circadian Disorder were specifically excluded from the study as well as those with technically compromised polysomnograms (including those where percentage failure of flow signal was 20% or greater) and where Time In Bed (TIB) was <7 h or >9 h. The study received formal approval by the Clinical Lead for sleep and Institutional Review Board of our hospital. 3. Statistical analysis Statistical analysis was performed using SPSS 20.0 (IBM Corp Rel 2011; IBM SPSS Statistics for Windows V 20 Armock NY). Data are presented as group mean and with standard deviations. A 3-way ANOVA was used to evaluate between-group interactions, with alpha set at 0.05. A 2 way ANOVA was used to evaluate the difference between 2 groups. A Pearson's Correlation coefficient was also used to delineate the nature of PTT changes with variables underlying sleep disordered breathing and other key demographics. Statistical significance was defined as a p value < 0.05. 4. Results 20 subjects (AHI 3.84 (SD 1.16)), identified as meeting criteria for inclusion in the IFL cohort, were aged and gender matched with 20 subjects meeting criteria for OSAS (AHI 49.93 (SD 16.77)) as well as 20 subjects with no evidence of significant sleep disordered breathing (“NFL” cohort; AHI 1.01 (SD 1.05)). Table 1 outlines key demographics in the IFL, OSAS and NFL subjects. Of the 20 subjects in the NFL cohort, 14 presented with “simple snoring” in the absence of EDS, 2 presented with insomnia, 2 with nightmares, 1 with parasomnia and 1 with generalised fatigue. 13 subjects (65%) in the IFL cohort were female. The mean BMI of the IFL cohort was significantly higher than the NFL cohort (ANOVA 34.25 (6.63) v 28.90 (6.61); 95%CI 1.06e9.67; F ¼ 6.36 p ¼ 0.016). The mean BMI of the IFL cohort was not found to differ significantly
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Table 1 Key demographics in the IFL, OSAS and NFL “Control” cohorts.
Age (years) BMI (kg/m2) AHI (per hour) RDI (per hour) ODI(per hour) Mean Oxygen Saturation Snore Index PTT Arousal/Deceleration Index (PTT Ar) PTT Incremental Index (PTT IncI) Epworth Sleepiness Score (ESS) at presentation Presence of Hypertension Presence of Cardiac Disease
Inspiratory Flow Limitation (IFL) Cohort (n ¼ 20; female ¼ 13)
Obstructive Sleep Apnoea Syndrome (OSAS) Cohort (n ¼ 20); female ¼ 13
“NFL” Control Group (n ¼ 20; female ¼ 13)
F Value
P value
47 (8.39) 34.25 (6.63) 3.84 (1.16) 17.71 (5.34) 4.49 (2.37) 95.05 (1.85) 210.73 (173.11) 33.67 (23.34) 34.56 (24.27) 16.35 (3.65) 5/20 1/20
45 (8.30) 36.31 (5.62) 48.93(16.77) 57.56 (16.00) 40.42 (15.52) 93.75 (1.55) 305.76 (175.54) 55.21 (29.30) 56.59 (31.00) 14.45 (5.52) 5/20 1/20
47 (8.79) 28.90 (6.81) 1.01 (1.05) 2.63 (1.34) 1.18 (1.47) 95.90 (1.48) 73.39 (66.74) 23.89 (18.88) 25.30 (18.34) 7.90 (6.21) 0/20 0/20
F ¼ 0.28 F ¼ 7.21 F ¼ 152.78 F ¼ 159.72 F ¼ 114.21 F ¼ 10.14 F ¼ 12.55 8.76 8.19 F ¼ 12.49 F ¼ 3.16 F ¼ 0.5
P P P P P P P P P P P P
from the OSAS cohort (ANOVA; 34.25 (6.63) v 36.31 (5.62); 95% CI -5.99e1.88; F ¼ 1.12 p ¼ 0.30). When combining the OSAS, IFL and NFL cohorts, a significant correlation was noted between the PTT Ar and PTT Inc (CC ¼ 0.993; p < 0.001). The PTT Ar in the IFL cohort (33.67±(23.34)/hr) was significantly higher than that measured in the NFL cohort (23.89 ±(18.88)/hr) denoting a higher degree of cardiovascular arousal in the IFL cohort. The greatest level of cardiovascular arousal was noted in the OSAS cohort who exhibited the highest PTT Ar (55.21± (29.30)/hr; 3-way ANOVA; F ¼ 8.76; p < 0.001; see Fig. 1). The PTT Ar was also found to correlate significantly with the AHI (CC ¼ 0.46; p < 0.001) and the ODI (CC ¼ 0.47; p < 0.001) of the study population. A statistically significant correlation was also observed between PTT Ar and the RDI of the study population (CC ¼ 0.49; p < 0.001) suggesting that the extent of cardiovascular increased with the degree of sleep-disordered breathing when encompassing hypopnoeas accompanied by desaturation, apneas as well as flow limited breaths resulting in RERAs (see Fig. 2; R2 ¼ 0.24). A non-significant trend in correlation was observed between
¼ 0.76 ¼ 0.002 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 ¼ 0.001 < 0.001 ¼ 0.05 ¼ 0.61
PTT Ar and age (CC ¼ 0.29; p ¼ 0.07). No significant correlation was reported between PTT Ar with BMI (CC ¼ 0.16; p ¼ 0.22) or Epworth Score (CC ¼ 0.03; p ¼ 0.84). 5. Discussion The presence of nocturnal inspiratory flow limitation without associated oxygen desaturation is a finding which may be overlooked by clinicians who use Home Sleep Testing to rule in or out the diagnosis of OSAS. Our study has shown that the PTT Arousal Index was greater in adult subjects presenting with EDS and exhibiting nocturnal IFL in comparison to a group exhibiting no evidence of SDB. This supports the hypothesis that the presence of nocturnal IFL represents a potentially significant pathogenic entity in the development of daytime sleepiness. Furthermore, we propose that the demographics reported in our IFL cohort raises potential gender differences in the pathophysiology of SBD. Females constituted 65% of the IFL cohort in contrast to the literature in OSAS where traditionally, a male predominance is described [13]. We reported that the BMI of the IFL cohort (mean BMI of 34.25 kg/
Fig. 1. Relationship between PTT arousal (Deceleration) index and sleep disordered breathing (by category: IFL, OSAS and NFL cohort).
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Fig. 2. The relationship between PTT arousal (Deceleration) index and RDI.
m2) did not differ significantly from the OSAS cohort. This suggests that a subset of obese predominantly female individuals may present with EDS related to IFL rather than exhibiting apnoeas or hypopneas associated with desaturation. Detailed studies are needed to gain a better understanding of the mechanism by which females may have a propensity to develop IFL resulting in daytime sleepiness. Such studies should include quantification of visceral fat distribution in IFL subjects, particularly in relation to gender. Interestingly, our study also reported a higher ESS in the IFL cohort when compared to the OSAS subjects. Whilst this may be explained by the fact that the IFL cohort was a selected population of matched subjects specifically referred with EDS, further studies are required to better understand key clinical and physiological differences between the IFL and OSAS cohorts. The highest PTT Arousal Indices were seen in the OSAS cohort exhibiting a mean Arousal Index greater than 55 events/hour. A study of paediatric subjects with OSAS, Upper Airways Resistance Syndrome (UARS), primary snorers and healthy subjects reported that the PTT Ar did not significantly differ between the OSAS and UARS groups, but was significantly lower in primary snorers and “healthy normals” [14]. However, this study included only subjects with a mild degree of OSAS with a mean AHI 10.6 compared to 48.9 events/hour in our OSAS cohort this potentially accounting for the greater difference in PTT Ar reported in our study. A study of 144 subjects with OSA revealed that the correlation between the PTT Arousal index and AHI was 0.44, a value similar to our OSA cohort [15]. Our study found that the PTT Arousal index was also found to correlate with the RDI, an index encompassing the degree of IFL. A study of OSAS patients randomised to CPAP aiming either to suppress IFL as well as apnoeas and hypopneas or to abolish only apnoeas and hypopneas reported a greater scatter in Maintenance of Wakefulness Test values and decreased CPAP usage in the latter group [16]. Further studies are required to determine whether CPAP therapy aiming primarily to reduce the PTT Arousal Index through abolishing flow limitation as opposed to reducing AHI alone might lead to superior clinical outcomes. A limitation of our study is in the utilisation of cardio-
respiratory polygraphy rather than PSG. However, in our study, all polygraphs were manually interpreted by a senior sleep physiologist using direct visual analysis and this has been demonstrated to be more aligned to a “polysomnographic” AHI when compared to automated analysis [17]. Furthermore, we used specific set criteria to define a “flow limited” event demonstrated to correspond to RERAs on PSG as demonstrated by Ayappa et al. [6]. Nonetheless, it is important to stress that the findings of our study apply only to subjects with IFL diagnosed under specific criteria along with presenting with EDS and this cannot be extrapolated to subjects presenting with IFL but with the absence of daytime impairment. It is also important to consider the limitations of interpreting PTT in clinical practice. For example, PTT indices may be affected by sleep fragmentation due to external stimuli or non-respiratory events, the occurrence of artefact (interference with the photoplethysmographic signal at the finger and disruption of ECG leads affected by chest wall movement) and during the presence of marked respiratory variation particularly during REM sleep [8]. This may be a factor contributing to the elevated PTT Arousal Index in the “NFL” subjects exhibiting no evidence of SDB.
6. Conclusion In summary, this study demonstrates that the PTT Arousal Index, a marker of sleep fragmentation, was found to be significantly higher in a group of subjects presenting with EDS exhibiting inspiratory flow limitation in comparison to subjects exhibiting an absence of sleep disordered breathing supporting the concept that the occurrence of nocturnal flow limited breathing may represent a relevant mechanism in the pathogenesis of daytime sleepiness.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Contributorship BC, SC, ND and JFOR conceived and designed the research. BC, SE and JFOR acquired, analysed and interpreted the data. BC drafted the manuscript and BC, SC, ND and JFOR revised it critically for important intellectual content. Competing interests Nil. References [1] J.R. Stradling, R.J.O. Davies, Sleep. 1: obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history, Thorax 59 (1) (2004) 73e78. [2] C. Guilleminault, R. Stoohs, A. Clerk, J. Simmons, M. Labanowski, From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness, Sleep 15 (6 Suppl) (1992) S13eS16. [3] American Academy of Sleep Medicine, International Classification of Sleep Disorders, third ed., American Academy of Sleep Medicine, Darien, IL, 2014. [4] G. Calero, R. Farre, E. Ballester, L. Hernandez, N. Daniel, J.M. Montserrat Canal, Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome, Respir. Med. 100 (5) (2006) 813e817. [5] L.O. Palombini, S. Tufik, D.M. Rapoport, Ia Ayappa, C. Guilleminault, L.B.M. de Godoy, L.S. Castro, L. Bittencourt, Inspiratory flow limitation in a normal ~o Paulo, Brazil, Sleep 36 (11) (2013) 1663e1668. population of adults in Sa [6] I. Ayappa, R.G. Norman, A.C. Krieger, A. Rosen, R.L. O’malley, D.M. Rapoport, Non-Invasive detection of respiratory effort-related arousals (RERAs) by a nasal cannula/pressure transducer system, Sleep 23 (6) (2000) 763e771.
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