Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03232658 |
| Other study ID # |
0006-17-LOE |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2018 |
| Est. completion date |
December 2020 |
Study information
| Verified date |
February 2019 |
| Source |
Loewenstein Hospital |
| Contact |
Arie Oksenberg, PhD |
| Phone |
+972 544755738 |
| Email |
arieo[@]clalit.org.il |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Obstructive sleep apnea (OSA) is a common nocturnal breathing disorder characterized by
complete (apnea) and partial (hypopnea) breathing cessations during sleep. Currently,
clinical diagnosis of OSA is based on the clinical symptoms, especially excessive daytime
sleepiness, and apnea-hypopnea index (AHI) providing a limited overview of the breathing
cessation event frequency during the night. Longer obstruction events and deeper
desaturations have been suggested to be more harmful than shorter and shallower events and
these individual characteristics are completely neglected by conventional and currently used
AHI.
The investigators have previously introduced novel diagnostic parameters incorporating the
number, duration and morphology of individual obstruction events and shown that they improve
the severity estimation of OSA compared to traditional measures. Even though, the novel
diagnostic parameters have so far tackled some of shortcomings of AHI, they need to be
refined to further increase the accuracy of the OSA severity estimation.
It has been shown that age, body mass index (BMI) and sleeping position are strongly related
to the severity OSA. However, it is not thoroughly studied whether the severity of individual
obstruction events progress over time (the aging process) and which factors affect to this
progression. It is known that OSA patients with similar AHI values, durations of individual
breathing cessation events can differ significantly. Longer and deeper events are connected
to increased mortality rate in patients with moderate or severe OSA and thus, could be
considered to be more detrimental than shorter and shallower ones. However, it has not been
thoroughly investigated whether in severe OSA patients with identical AHI values, sleep
efficiency or hypertension is related to the severity of individual breathing cessation
events.
The investigators planned to explore, whether the individual breathing cessation event
severity progress over time and how different confounding factors affect this progression.
Furthermore, the correlation of EDS with the individual breathing cessation event severity,
sleep structure, and frequency and occurrence of cortical arousals will be investigated.
Also, the investigators will explore whether the percentage time of disturbed breathing from
total sleep time is related to sleep efficiency or hypertension in severe OSA patients having
similar AHI. Moreover, Positional therapy (PT) i.e., the avoidance of the supine posture
during sleep is the treatment of choice for Positional Patients (PP) having most of their
breathing abnormalities while sleeping supine. Since it is known that apneas/hypopneas are
more severe while sleeping supine, this time the investigators will assess the therapeutic
value of PT for severe Non Positional patients (NPP).
Description:
Obstructive sleep apnea (OSA) is a prevalent nocturnal breathing disorder characterized by
complete (apnea) and partial (hypopnea) breathing cessations during sleep 1. OSA is connected
to cardiovascular disease, increased mortality rate and impairment of quality of life 2-4.
Its prevalence has been estimated to be 9-27 % among middle-aged population and the
prevalence is expected to increase in the future 5,6.
Currently, the most commonly used diagnostic parameter for OSA is apnea-hypopnea index (AHI)
based on number of apneas and hypopneas during sleep, neglecting their durations and also
durations and depths of related desaturation events. In adults OSA is diagnosed if patient
has 1) AHI≥5 events/h with associated symptoms (e.g. excessive daytime sleepiness (EDS)) or
medical or psychiatric disorder (e.g. hypertension or mood disorder) or 2) AHI≥15 events/h 7.
Previously, the investigators have introduced novel parameters called as obstruction
severity, obstruction duration, desaturation severity, desaturation duration, and
adjusted-AHI incorporating number, duration and morphology of individual obstruction events
(i.e. apneas, hypopneas, and oxygen desaturations) 8,9.we have shown that these parameters
can enhance the severity estimation of OSA and that the individual breathing cessation event
severity is more strongly connected to increased mortality and cardiovascular morbidities
than conventional AHI8,10,11. The potential of these parameters to enhance the assessment of
severity of OSA has been previously investigated only using ambulatory polygraphic recordings
without EEG registration. Therefore, the parameters do not take into account hypopneas
followed by arousal (but not desaturation). In addition, parameters do not take into account
apneas not followed by desaturation and novel parameters need to be refined to take into
account also such events in order to further increase their prognostic value.
It is known that age and body mass index (BMI) are positively related with the prevalence of
OSA12,13. Furthermore, AHI is higher and apneas longer in supine position compared to lateral
position14-16. However, it is not thoroughly explored whether the severity of individual
obstruction events progress over time and which factors affect to this progression.
EDS is a common symptom of OSA and it can be measured in various methods. The most widely
used methods are Epworth Sleepiness Scale (ESS) questionnaire which measures subjective
sleepiness and Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT)
which measure sleepiness objectively. However, the correlation between ESS score and the
severity of OSA (i.e. number of obstruction events) have been shown to be poor 17.
Furthermore, albeit MSLT and MWT have been shown to have better correlations with daytime
functions than ESS their correlations with AHI and arousal index still remainsweak18.
Therefore, it needs to be investigated whether the severity of individual breathing cessation
events is correlated better with MSLT and MWT and thus, explaining with more accuracy the
daytime symptoms.
It has been shown that between patients with identical AHI values, durations of individual
apneas and hypopneas and durations, depths, and areas of individual desaturations can differ
significantly 19. Longer and deeper obstruction events could be considered to be more harmful
than shorter and shallower events as they are linked to increased mortality rate in patients
with moderate or severe OSA 8. Nonetheless, it has not been thoroughly investigated whether
in severe OSA patients with identical AHI values sleep efficiency or hypertension is related
to the severity of individual breathing cessation events and if this relationship is
modulated by sleeping position.
Positional therapy (PT), the avoidance of the supine posture during sleep is the treatment of
choice for Positional Patients (PP) who have only or most of the apneas/hypopneas while
sleeping in the supine posture 22. Non positional patients (NPP) have many apneas/hypopneas
while sleeping in both, the supine and the lateral posture. For these patients Continuous
Positive Airway Pressure (CPAP) is the treatment of choice, however, many patients have
strong difficulties to adhere to CPAP and thus, the investigators would like to assess the
therapeutic value of PT for these NNP. Since apneas/hypopneas are more severe while sleeping
in the supine than in the lateral posture.15, 16 PT for these patients could represent a
valuable treatment. This is an issue that the investigators also want to assess in this
project.
In this research project the investigators aim to tackle these shortcomings in the
diagnostics of OSA. The main aim is to improve the severity estimation of OSA by further
refining the novel parameters for diagnostics of OSA. These improvements to the parameters
will be done in order to prevent the harmful consequences of the disease and to be able to
target the limited treatment resources to those in the greatest need.
2. HYPOTHESES AND AIMS
In this research project the investigators tackle the limitations of AHI and refine the novel
parameters introduced in our earlier papers. To achieve this, four aims will be undertaken.
The first aim is to explore, whether the severity of individual breathing cessations
progresses over time and how different confounding factors (e.g. BMI, sleeping position, and
gender) affect this progression. The investigators believe that individual event
characteristics have a major role in the overall severity of OSA. The current knowledge on
the progression of OSA is limited to number of events while the detailed changes in the
individual event characteristics has not been thoroughly explored before. This is a major
shortcoming as event severity can be considered clinically significant and have been
associated with the risk of OSA related mortality and cardiovascular morbidity. The second
aim is to improve our recently developed novel parameters to provide even more accurate
severity estimation by including more detailed analysis of hypopnea events followed by
arousal and apnea events that do not induce desaturations. This more detailed analysis can
enhance the estimation of OSA related mortality and incidence of comorbidities and improve
the discrimination of patients needed to be treated but it can also help clinicians to choose
best individualized treatment method for each patient. The third aim of the research project
is to evaluate the correlation of excessive daytime sleepiness (EDS) with the individual
breathing cessation event severity, sleep structure, and frequency and occurrence of cortical
arousals. As EDS is a major problem reducing the quality of life, finding effective measures
to recognize factors behind EDS could aid to enhance the treatment of these patients and
improvement of their life quality. The fourth aim is to explore whether the percentage time
of disturbed breathing from total sleep time is related to sleep efficiency or hypertension
in severe OSA patients having similar AHI values and whether this percentage alters depending
on confounding factors (e.g. BMI, hypertension, and proportion of supine sleep). More
detailed characterization of severe OSA patients could aid the clinicians to recognize the
patients with most urgent need for effective treatment.
The fifth aim is to assess the therapeutic value of positional therapy (PT) for severe NPP.
This assessment is of interest since many severe OSA patients that should be treated with
CPAP are not been treated due to the difficulties to adhere to CPAP treatment. This
behavioral treatment could represent a partial solution until these patients lose weight,
consider surgery (ENT or bariatric) or the use of dental appliance or give to CPAP another
chance.
It is important to note that by losing weight NPP may become PP 23 and thus, PT could
represent no a partial but a more radical solution.
2. RESEARCH PLAN AND METHODS
The planned research includes five work packages designed to enable reaching the project
aims.
Work package I: Progression of individual obstruction events over time - retrospective
follow-up study In this package,we will explore how the duration of individual apnea and
hypopnea events and duration, depth and area of individual desaturation events progress over
time. It will be investigated how different confounding factors (e.g. age, BMI, sleeping
position and gender) affect the progression of the individual breathing cessation event
severity. This package is based on polysomnographic (PSG) recordings of about 400 patients
with suspected OSA recorded with Embla (Natus Medical Incorporated, Pleasanton, CA, USA) or
Rembrandt (Natus Medical Incorporated, Pleasanton, CA, USA) devices and analyzed using
RemLogic software at the Sleep Disorders Unit, Lowenstein Hospital - Rehabilitation Center,
Raanana, Israel. For all patients, two - three PSG recordings were conducted at different
time points, at baseline, and after 3, 5, 10 years or more. These polygraphic recordings were
analyzed in conformity with the standard respiratory rules specified by AASM and based on
clinical practice in Lowenstein Hospital at the time of analysis. Based on the analyzed
recordings, the severity of individual obstruction events will be calculated using
custom-made MATLAB (Matlab R2014b, MathWorks Inc., Natick, MA, USA) functions. Severity of
individual obstruction events will be compared between the different time points for each
patient and in a group level. Grouping of the patients will be done based on the confounding
factors (e.g. patients' BMI, gender, sleeping position, AHI, and age).
Work package II: Optimization of the diagnostic parameters of OSA which incorporates the
severity of individual breathing cessation events In this package, the novel parameters will
be further refined by adding features to also include apneas not followed by desaturations
and hypopneas followed by arousal (but not desaturation). Furthermore, the aim is to evaluate
whether apneas should be given more weight than hypopneas while estimating the overall
severity of OSA. In this package, in-laboratory PSG recordings (n=7540) including EEG
conducted and analyzed at the Sleep Disorders Unit, Lowenstein Hospital - Rehabilitation
Center for the patients with clinical suspicion of OSA will be studied. The basic
anthropometric data and information on mortality and co-morbidities will be also collected.
All recordings were analyzed according the standard respiratory rules defined by AASM and
based on clinical practice in Lowenstein Hospital. Novel parameters and severity of
individual obstruction events will be calculated using custom-made MATLAB functions. The
calculated severity indexes based on enhanced and the original obstruction severity
parameters will be compared with incidence of OSA related mortality and co-morbidities.
The information on mortality, cause of death and co-morbidities hopefully will be obtained
from the Ministry of Health.
Work package III: Effect of severity of individual obstruction events on excessive daytime
sleepiness In this package, the investigators investigate the correlation between the
severity of individual breathing cessation events and excessive daytime sleepiness measured
with objective means (i.e. Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness
Test (MWT)). Furthermore, it will be studied which information obtained from PSG recordings
(e.g. frequency and duration of cortical arousal, sleep structure or severity of individual
obstruction events) is best correlated with excessive daytime sleepiness and therefore, would
be beneficial to take into account while estimating the severity of OSA. Clinical
in-laboratory PSG recordings (n=3000) of patients with suspected OSA, conducted and analyzed
at the Sleep Disorders Unit, Lowenstein Hospital - Rehabilitation Center with the Embla
devices and RemLogic software, will be used. The values of the novel parameters and the
severity of individual obstruction events will be calculated using custom-made MATLAB
functions and their correlation on results of objective tests measuring excessive daytime
sleepiness (i.e. MSLT and MWT) will be investigated.
Work package IV: Differences in severity of individual obstruction events between patients
having severe OSA In this package, the severe OSA patients will be matched by AHI and the
percentage time of disturbed breathing from total sleep time will be compared between these
patients. The patient population consists of 463 patients diagnosed to have severe OSA after
full overnight PSG recording conducted at the Sleep Disorders Unit, Lowenstein Hospital -
Rehabilitation Center. It will be studied whether the percentage time of disturbed breathing
from total sleep time differs between the patients having similar AHI and whether it is
related to different outcome measures (e.g. hypertension and sleep efficiency). Furthermore,
it will be investigated whether this percentage is modulated by different confounding factors
(e.g. gender, BMI, and sleeping position).
Work package V: The assessment of the therapeutic value of Positional Therapy for severe Non
Positional Patients (NPP) In this package the investigators we will assess the therapeutic
value of Positional Therapy (PT) i.e., the avoidance of the supine posture during sleep, as a
treatment alternative for severe Non Positional Patients (NPP) who failed to adhere to
Continuous Positive Airway Pressure (CPAP). The patient population consists of the same 463
patients diagnosed to have severe OSA after full overnight PSG recording conducted at the
Sleep Disorders Unit, Loewenstein Hospital - Rehabilitation Center. In this group of patients
the investigators will assess the effect of sleeping only in the lateral posture (PT) and the
assessment of the severity of the disease will be calculated according to conventional and
new methods developed previously by our research group.
