Rehabilitation Program as an Alternative Therapy for Moderate to Severe Obstructive Sleep Apnea Syndrome
Condition: Sleep Apnea, Obstructive; Metabolic Syndrome
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Metabolic Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      The obstructive sleep apnea/hypopnea syndrome (OSAS) is a common disease (2-4% of the general
      population) that generates intermittent hypoxemia and sleep fragmentation. OSAS is associated
      with various metabolic disorders such as metabolic syndrome, type 2 diabetes. OSAS is a risk
      factor for cardio-vascular diseases by increasing morbidity/mortality. OSAS patients suffer
      from excessive daytime sleepiness (EDS), a symptom also responsible for at least 30% of
      traffic accidents but also other cognitive disorders with significant impact on quality of
      life. OSAS generates oxidative stress, inflammation and resistance to insulin and other
      systemic metabolic dysregulation of many whose levels are correlated with the severity of the
      disease.

      Treatment with Continuous Positive Airway Pressure (CPAP) has clearly demonstrated its
      effectiveness to eliminate apneas and improve EDS but it is sometimes difficult to accept
      and/or poorly tolerated, limiting its effectiveness.

      Weight loss and regular physical activity are clearly recommended but rarely done in clinical
      practice. A few studies have applied to study the effects of rehabilitation training (REE) on
      the sleep apnea patients and have shown an improvement in sleep quality, reduction of
      awakenings and arousals from sleep and the Index of Apnea/Hypopnea (AHI), but their
      methodology was questionable, and the number of patients included was too low.

      The investigators hypothesis is that an in-patient multidisciplinary rehabilitation program
      comprising educational activities, dietary management and individualized exercise training
      (IET) will decrease OSAS severity, improve sleep quality and symptoms (EDS, fatigue, QoL).
      This IET program (24 sessions during 4 weeks) could also help to improve many metabolic
      dysregulation, inflammation and oxidative stress (also markers of cardiovascular risk).
      Leptin, a hormone involved in regulating appetite, energy expenditure and ventilatory control
      is increased in OSA (mechanism of leptin resistance). The improved sensitivity to leptin may
      play a role in enabling a better control of ventilation in these patients.
    

Detailed description: 
      The obstructive sleep apnea/hypopnea syndrome (OSAS), with an estimated prevalence of between
      2 and 4% (1) is characterized by repetitive obstructions of the upper airway that generate
      intermittent hypoxemia and sleep fragmentation. The typical clinical profile of the apneic
      patient is an middle aged (50-55 years) obese male, snoring and drowsy. Moreover, OSAS is a
      risk factor for hypertension independent of obesity (2, 3) and it is now clear evidence that
      untreated apnea patients have high cardiovascular morbidity / mortality (CVM) higher than
      subjects treated with CPAP (4-6).

      Clinically, excessive daytime sleepiness (EDS) is the main symptom (7) but the attentional
      and cognitive disorders (8.9), depression or simply a state of fatigue are other possible
      manifestations of OSAS. The impact on quality of life (QoL) (10-12) are significant and
      underestimated. The origins of this drowsiness are multiple: one finds the fragmentation of
      sleep (13,14), intermittent hypoxia, respiratory effort, obesity (15) and certain cytokines
      such as TNF-alpha and IL-6 involved in sleep regulation (16-19).

      On the pathophysiology, the investigators find in the obstructive apneic oxidative stress
      (20-24) and systemic inflammation (25-27). CRP and levels of some cytokines (IL-1 beta, IL-6,
      IL-8 and TNF-alpha) are increased and their levels are correlated with the severity of
      disease as the increase of CVD (28-30 ). Intermittent hypoxia appears to play an essential
      role in the genesis of these abnormalities (31).

      On the metabolic dysregulation of many coexist. Found abnormal fasting blood glucose, a state
      of insulin resistance, dyslipidemia, and hyperleptinemia. Insulin resistance increases with
      body weight independent of the index of apnea / hypopnea (AHI) (18, 32-34). Intermittent
      hypoxia appears to be the cause. Leptin secreted by adipocytes, regulates weight by
      controlling appetite and energy expenditure. The hyperleptinemia found in OSA is
      controversial. Obesity appears to be primarily responsible for some (36) while others suggest
      the role of nocturnal hypoxemia (37). In fact, it is more the state of leptin resistance that
      hyperleptinemia alone that seems to be involved.

      Treatment with continuous positive airway pressure (CPAP) has clearly demonstrated its
      effectiveness to suppress apneas and sleep fragmentation associated. A meta-analysis (38) has
      confirmed the improvement of IDS by the PPC. However, in less severe forms, improving the SDE
      is less clear (39) and the PPC is sometimes not easily accepted, not tolerated and limiting
      its effectiveness is its poor compliance (40,41). From a pathophysiological point of view,
      CSF improves systemic inflammation (26,27) and diminishes the CVD (5.6). For cons, the
      metabolic dysregulation (insulin resistance, hyperleptinemia, dyslipidemia) are improving
      somewhat CPAP except in patients without obesity (42-44).

      The dietary guidelines are essential for the management of this disease is the result for a
      large part of a healthy lifestyle deleterious. Weight loss, regular physical activity is also
      clearly recommended but unfortunately rarely performed and / or supported by our healthcare
      system. Few studies have focused on studying the effects of such treatment on sleep apneic
      patients. In normal subjects, the effects of exercise on sleep are described in a
      meta-analysis (45). The practice of regular physical activity endurance improves quality of
      sleep (45-47). Sleep latency is shorter, there is less change in stages and fewer awakenings
      and arousals from sleep. Unlike other studies show that in situations where physical activity
      is reduced (physical inactivity, obesity, or prolonged bed rest, for example) sleep
      deteriorates, breaks and daytime alertness decreases. The effect of exercise in OSAS (48,49)
      and especially the training in physical exercise (48) shows an improvement in sleep quality
      and reduction of awakenings and arousals from sleep and fewer respiratory events (IAH).
      Pathophysiological point of view, there is a decrease in concentrations of leptin (50-53) and
      inflammatory cytokines (54-55) in different populations of subjects (healthy, older, obese,
      or with heart failure). And the investigators know the effects of exercise on carbohydrate
      metabolism in particular (decreased insulin resistance).

      And physical activity improves sleep quality in normal subjects while in parallel it would
      have an anti-inflammatory. For patients with severe OSAS, our hypothesis is to improve the
      quality of sleep (SLP rate) and a decrease in AHI and EDS through rehabilitation training
      (REE) associated with a comprehensive care (patient education, dietary, psychological, ...).
      On the pathophysiology, this improvement would be through a reduction of biological
      abnormalities associated with OSA are also markers of cardiovascular risk. Mainly metabolic
      disorders, oxidative stress and systemic inflammation.
    

Intervention name(s): In-patient rehabilitation; Educational activities alone
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Individualized exercise training (IET):
Duration : 24 sessions during 4 weeks
IET session (2h) contains:
15' start warming up muscles
30' muscle strengthening exercise for arms and abdominal muscles
45' individualized cycle ergometer endurance training to the ventilatory threshold heart rate measured on the cardiopulmonary exercise test.
15' stretching
15' postural, movement and balance exercises IET session was controlled by a professional instructor using heart rate monitoring. Duration, intensity and attendance were recorded in a logbook.
Educational activities (20h): the 8 themes are comparable to comparator arm. Dietary management: was performed by dietician to ensure that energy intakes are adjusted to energy expenditure. No restrictive diet was prescribe.; Educational activities alone contains 10 sessions lasting 1:00 with 8 themes :
Physiological mechanisms of apneas/hypopneas
Effects of apneas/hypopneas on health (vascular morbidity/mortality and sleepiness)
Beneficials effects of CPAP and/or advanced mandibular orthosis
Description of sleep stages and physiological roles of sleep
Known effects of exercise on sleep and metabolism
Importance of good nutritional status and sleep hygiene on quality of life
How to apply theses lessons of rehabilitation in daily life
Other intervention name(s): Individualized exercise training; Educational activities; Dietary management; Educational activities
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Obstructive Sleep Apnea/Hypopnea Syndrome; Exercise training program; Inflammation; Oxidative Stress; Resistance to insulin