Effect of Continuous Positive Airway Pressure (CPAP) on Systemic Blood Pressure, Coagulability and Carotid Intima-media Thickness in Patients With Sleep Apnea
Condition: Obstructive Sleep Apnoea
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Interventional

Summary: 
      Sleep-disordered breathing (SDB) briefly means cessation of breathing during sleep at least 5
      times per hour. Sleep-disordered breathing affects 9 to 24% of the middle-aged and overall 4%
      of the middle-aged males suffers from Obstructive sleep apnea syndrome (OSAS) i.e. SDB with
      associated daytime sleepiness. Several major epidemiological studies have shown that SDB is
      not only an independent risk factor for systemic hypertension but it is also associated with
      cardiovascular complications such as heart failure, stroke, and sudden death.

      The mechanisms for the linkage between Sleep-disordered breathing and cardiovascular diseases
      are not fully determined but surges in sympathetic nerve activity are seen at the end of each
      apneic episode accompanied by large rises in systemic arterial blood pressure (BP). The
      increased levels of muscle sympathetic nerve activity are diminished by nasal continuous
      positive airway pressure (CPAP) therapy. Numerous studies have found a hypercoagulable state
      in terms of increased clotting factor and platelet activities, and impaired fibrinolysis in
      coronary artery disease, ischaemic stroke, and sleep-disordered breathing. Common carotid
      artery intima-media thickness (IMT) has been shown to correlate with traditional vascular
      risk factors and may predict the likelihood of acute coronary events and stroke. Recently,
      carotid artery intima-media thickness has been shown to have positive correlations with the
      severity of sleep disordered breathing.

      Despite robust evidence showing improvement of symptoms, cognitive function and quality of
      life in patients with obstructive sleep apnea treated with nasal continuous positive airway
      pressure, there are conflicting short-term data whether continuous positive airway pressure
      can reduce blood pressure in patients with obstructive sleep apnea. This randomized
      controlled study aims to assess the long-term effects of nasal continuous positive airway
      pressure on 1) 24 hr systemic blood pressure; 2) Coagulation state; and 3) Carotid artery
      intimal media thickness.
    

Detailed description: 
      Subjects and Methods: We propose to carry out a prospective, randomized controlled study on
      100 consecutive patients newly diagnosed with obstructive sleep apnea syndrome, as defined by
      overnight sleep study showing Apnea- hypopnoea index (AHI) >or=5 per hour of sleep plus
      Epworth sleepiness scale (ESS) ≥10.1 The patients will be recruited from the Respiratory
      Clinic, Prince of Wales Hospital (PWH), Shatin.

      Sleep assessment: Overnight diagnostic polysomnography(PSG) [Healthdyne Alice 4, USA] will be
      performed at Prince of Wales Hospital, Hong Kong for every subject on the first night
      recording electroencephalogram, electro-oculogram, submental electromyogram, bilateral
      anterior tibial electromyogram, electrocardiogram, chest and abdominal wall movement by
      inductance plethysmography, airflow measured by a nasal pressure transducer [PTAF2, Pro-Tech,
      Woodinville, WA, USA]and supplemented by oronasal airflow thermister, and finger pulse
      oximetry as in our previous studies.2,3 Sleep stages will be scored according to standard
      criteria by Rechtshaffen and Kales.4 Apnoea is defined as cessation of airflow for > 10
      seconds and hypopnea as a reduction of airflow of > 50% for > 10 seconds plus an oxygen
      desaturation of > 3% or an arousal.

      Ambulatory Blood Pressure Monitoring (ABPM):

      All patients with obstructive sleep apnea syndrome will be fitted with the Ultralite
      Ambulatory Blood Pressure Monitoring (Spacelabs Medical, Redmond, WA) via an arm cuff as
      out-patients during normal activities and monitored for 48 hrs prior to commencement of
      continuous positive airway pressure or conservative treatment. The patients' arm
      circumference will be measured at the biceps level and an appropriate sized arm cuff will be
      applied. The machine will be programmed for cuff inflation measurement every 30 minutes for
      48 hrs and can only be removed for bathing. Patients will be asked to abstain from
      caffeine-containing products during this time but to continue their normal daily activities.
      Patients will record the time they retire to bed and the subsequent time of waking in order
      to identify the sleep period. Data gathered before 6pm on the second evening will be
      discarded to allow for acclimatization and the analysis will be performed with the second 24
      hr of data (6pm to 6am).5 Data will be manually checked for artifact by our respiratory
      fellow, who will be blinded to the treatment status of the patient. Ambulatory Blood Pressure
      Monitoring will be repeated for all patients with significant OSAS at 3, 6, and 12 months of
      the study.

      Conservative treatment 6 months followed by continuous positive airway pressure 6 months vs
      Concurrent continuous positive airway pressure+ Conservative treatment for 12 months:

      Following confirmation of significant obstructive sleep apnea syndrome from the overnight
      sleep study with Apnoea hyponea index ≥ 5/hr and Epworth Sleepiness Scale ≥10 and completion
      of baseline Ambulatory Blood Pressure Monitoring, each patient will be interviewed by the
      physician on duty and randomized by computer into either Group 1) Conservative treatment for
      the first 6 months followed by therapeutic Continuous positive airway pressure for the next 6
      months or Group 2) Conservative treatment plus therapeutic Continuous positive airway
      pressure for 12 months. As sleepiness is the main indication for Continuous positive airway
      pressure treatment, we have decided that a randomized placebo controlled design is not
      feasible for this long-term study. The research nurse responsible for randomization of
      patients to different treatment arms will not participate in outcome assessments, which will
      be conducted by a different team of nurses who are not aware of the randomization status of
      the patients.6,7 Group 1: After confirmation of significant obstructive sleep apnea syndrome,
      the patients will be informed about the nature of their disease and the need to start
      treatment. They are encouraged to a) avoid sleep deprivation by having sufficient hours of
      sleep every night; b) sleep in lateral positions; c) avoid sedatives and alcohol consumption;
      and d) lose weight by following a home diet prescribed by a dietitian.8 The patients will be
      reviewed at the respiratory clinic at 1, 3 and 6 months to re-assess their sleepiness & body
      mass index. Ambulatory blood pressure monitoring will be repeated at 3, 6, and 12 months. On
      completion of the conservative treatment and evaluation including ambulatory blood pressure
      monitoring at 6 months, patients in group 1 will be started on therapeutic continuous
      positive airway pressure treatment, as outlined under group 2, after an overnight continuous
      positive airway pressure titration study.

      Group 2: Patients in the therapeutic continuous positive airway pressure arm will be given a
      short trial of continuous positive airway pressure therapy with the Autoset (Resmed, Sydney,
      Australia) device for approximately 30 minutes for acclimatization in the afternoon. Each
      patient will be given a basic CPAP education programme by our respiratory nurse supplemented
      by education brochure.2 Attended continuous positive airway pressure titration will be
      performed with the Autoset auto-titrating device on the second night of the polysomonograph
      study. All patients will be prescribed the Horizon LT 8001 continuous positive airway
      pressure device (De Vilbiss, Somerset, PA, USA) with a time counter recording machine run
      time. The continuous positive airway pressure pressure for each patient will be set at the
      minimum pressure needed to abolish snoring, obstructive respiratory events and airflow
      limitation for 95% of the night as determined by the overnight Autoset continuous positive
      airway pressure titration study. 2,3 The patients will be followed up at the Respiratory
      clinic at 1, 3, 6, and 12 months and the objective continuous positive airway pressure
      compliance will be measured from the time counter. All patients in each arm will be followed
      up at the Respiratory clinic regularly and the objective continuous positive airway pressure
      usage will be measured from the time counter.

      Other outcome assessment:

      Prior to commencement of conservative treatment or nasal continuous positive airway pressure
      , all patients have to go through several measurements. These include assessment of
      subjective sleepiness with the Epworth sleepiness scale (ESS),9 quality of life with the
      Calgary Sleep Apnoea Quality of Life Index (SAQLI), 10 hemostatic assays (DD, TAT,
      fibrinogen, vWF:ag),11 and evaluation of carotid artery initimal media thickness.12-14 The
      ESS is a questionnaire specific to symptoms of daytime sleepiness and the patients are asked
      to score the likelihood of falling asleep in eight different situations with different levels
      of stimulation, adding up to a total score of 0 to 24.9 The Calgary Sleep Apnea Quality of
      Life Index (SAQLI) has 35 questions organized into four domains: daily functioning, social
      interactions, emotional functioning and symptoms with a fifth domain, treatment-related
      symptoms, to record the possible negative impacts of treatment. It contains items shown to be
      important to patients with sleep apnea and is designed as a measure of outcome in clinical
      trials in sleep apnea.10 The early version of the Calgary Sleep Apnea Quality of Life Index
      (SAQLI) was applied previously to our study on Chinese obstructive sleep aonoea patients on
      continuous positive airway pressure 2 but an updated version will be applied to this study.15
      Carotid artery intimal media thickness will be assessed with B-mode Doppler according to a
      standardized scanning protocol for the right and left carotid arteries using images of the
      far wall of the distal 10 mm of the common carotid arteries as described by Woo et al
      previously.12-14 Carotid scans will be analyzed with a computerized edge-detection system
      that have previously been described and validated.12,16 Two end-diastolic frames are
      selected, digitized, and analyzed for mean intimal media thickness, and the average reading
      from these 2 frames is calculated for both right and left carotid arteries. The carotid scan
      operator is blinded to the identity of studied subjects and stage of the study.

      Hemostatic assays: After resting for 20 min in the sitting position, blood is obtained
      following the polysomongraphy recording through an indwelling 22-gauge venous forearm cannula
      that has been inserted the night before to minimize hemostatic activation due to emotions
      related to an impending venepuncture.11 The first 2 ml of blood will be discarded and another
      15 ml of blood will be drawn into sterile ethylenediamine-tetra acetic acid (EDTA)-
      containing tubes (Becton Dickinson Vacutainer Systems; Franklin Lakes, New Jersey, USA).
      Plasma samples are obtained by centrifugation in plastic tubes at -80C until further
      processing. Plasma TAT and DD levels are measured by ELIZA as per the manufacturers
      instructions (Enzyme Research Laboratories Inc., South Bend, Indiana, USA and Diagnostica
      Stago, Asnieres, France). Plasma fibrinogen levels (g/l) are determined using a commercially
      available assay (Thrombo-S, Dade Behring, Germany). Plasma levels of vWF:ag are measured
      following a previously described ELISA 17 using commercial antibodies (DAKO Corp.,
      Carpinteria, California, USA) and substrate (Bio-Rad Laboratories, Hercules, California,
      USA).

      Primary outcome of interest: Changes in mean systemic blood pressure between group 1 and
      group 2 at 6 months.

      Secondary outcome of interest: Changes in systolic and diastolic blood pressure between the 2
      groups at 6 & 12 months; serial changes of carotid intimal media thickness between the two
      treatment groups over 12 months; serial changes in hemostatic assays (TAT, DD, fibrinogen,
      vWF:ag) between the two groups at 1 month and 6 months after treatment; Continuous positive
      airway pressure compliance at 6, and 12 months; Epworth Sleepiness Scale (ESS) and the
      Calgary Sleep Apnea Quality of Life Index (SAQLI) at 1, 3, 6, and 12 months.
    

Intervention name(s): Continuous Positive Airway pressure; Placebo
Intervention type(s): Device; Other
Intervention description(s): Continuous positive pressure device with a time clock; Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment