Effect of Nasal Continuous Positive Airway Pressure (CPAP) Blood Pressure and Vascular Endothelial Growth Factor in Obstructive Sleep Apnea Syndrome
Condition: Obstructive Sleep Apnea
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. SDB is a common disorder affecting 9 to 24% of the middle-aged and overall 4%
      of the middle-aged male population suffers from the Obstructive sleep apnea syndrome (OSA)
      i.e. Sleep-disordered breathing (SDB) with associated daytime sleepiness. Several major
      epidemiological studies have shown that SDB is not only an independent risk factor for
      hypertension but it is also strongly associated with heart failure and stroke. The mechanism
      for the linkage between SDB and cardiovascular consequences is not fully determined. Vascular
      endothelial growth factor (VEGF) is a soluble 34-46 kD angiogenic heparin-binding
      glycoprotein. This cytokine regulates multiple endothelial cell functions including vascular
      permeability and vascular tone and some data suggest that it may contribute to the
      atherosclerotic process. Recent studies have shown increased plasma and serum concentrations
      of Vascular endothelial growth factor (VEGF) in patients with OSA and there were correlations
      between VEGF concentrations and the severity of OSA, as indexed by the minimum oxygen
      saturation level and the frequency of the upper airway obstruction per hour of sleep. A
      recent non-randomized study with a small sample size has shown a significant decrease in
      Vascular endothelial growth factor (VEGF) concentrations in patients in whom nocturnal
      hypoxia improved after 1 year of nasal continuous positive airway pressure (CPAP) therapy.

      Despite robust evidence showing improvement of symptoms, cognitive function and quality of
      life in obstructive sleep apnea (OSA) patients treated with nasal CPAP, there are
      nevertheless conflicting data whether Continuous positive airway pressure (CPAP) can reduce
      daytime blood pressure (BP) in patients with OSA. Two randomized placebo controlled studies
      have shown reduction of 24-hr systolic and diastolic blood pressure (BP) in obstructive sleep
      apnea (OSA) patients after 1 month of nasal continuous positive airway pressure (CPAP)
      therapy while other investigators have shown no such benefit.

      This randomized, sham-placebo controlled study aims to assess 1) the effect of nasal
      continuous positive airway pressure (CPAP) over a period of 3 months on 24 hr blood pressure
      (BP); and 2) whether any change in BP and plasma Vascular endothelial growth factor (VEGF) is
      related to the baseline severity of obstructive sleep apnea (OSA) and continuous positive
      airway pressure (CPAP) compliance.
    

Detailed description: 
      Subjects and Methods:

      We propose to carry out a prospective, randomized sham placebo-controlled parallel study on
      140 consecutive patients newly diagnosed with OSA, as defined by overnight sleep study
      showing apnea hypopnea index (AHI) >10 per hour of sleep plus excessive daytime sleepiness or
      two of the following symptoms: choking or gasping during sleep, recurrent awakenings from
      sleep, unrefreshed sleep, daytime fatigue and impaired concentration.1 The patients will be
      recruited from the Respiratory Clinic, Prince of Wales Hospital, Shatin, HK.

      Sleep assessment:

      Overnight diagnostic polysomnography (PSG) [Healthdyne Alice 4, USA] will be performed 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 an oral thermister, and
      finger pulse oximetry as in our previous studies.2-4 Sleep stages will be scored according to
      standard criteria by Rechtshaffen and Kales. 5 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.

      Following confirmation of significant obstructive sleep apnea syndrome (OSA) from the
      overnight sleep study with apnea hypopnea index (AHI) >10/hr, each patient will be
      interviewed by the physician on duty and randomized into 2 groups receiving either nasal
      therapeutic continuous positive airway pressure (CPAP) treatment or sham continuous positive
      airway pressure (CPAP), via a balanced block design, after completion of recording of 24 hr
      ambulatory blood pressure (BP).

      Ambulatory Blood Pressure Monitoring(ABPM):

      All patients with obstructive sleep apnea (OSA) will be fitted with the Ultralite Ambulatory
      Blood Pressure Monitoring (ABPM) (Spacelabs Medical, Redmond, WA) via an arm cuff as
      out-patients during normal activities and monitored for 48 hrs prior to commencement of
      therapeutic or sham continuous positive airway pressure (CPAP) 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).6 Data will be manually checked for artifact by our respiratory
      fellow, who will be blinded to the treatment status of the patient. Forty-eight hrs before
      the end of the therapeutic or sham continuous positive airway pressure (CPAP) at 3 months,
      the patients will be fitted with the Ambulatory Blood Pressure Monitoring(ABPM) machine and
      the same procedure repeated.

      Measurement of blood samples:

      Fifteen ml of fasting venous blood will be taken from each patient after the overnight PSG.
      Plasma will be separated within 2 hours in a refrigerated centrifuge, aliquoted and stored at
      -70C until assayed. Plasma VEGF will be measured by a quantitative enzyme-linked immunoassay
      technique using a commercially available kit (R & D Systems, Abingdon, UK). Serum lipids will
      be checked as it has been reported that Vascular endothelial growth factor (VEGF) also
      increases in patients with hyperlipidemia, with and without atherosclerosis.7

      Therapeutic continuous positive airway pressure (CPAP) vs Sham placebo:

      Patients in the therapeutic continuous positive airway pressure (CPAP) or sham continuous
      positive airway pressure (CPAP) treatment arm will be offered a 30-minute daytime trial of
      nasal continuous positive airway pressure (CPAP) treatment. Each patient will be given a
      basic continuous positive airway pressure (CPAP) education program by our respiratory nurse
      supplemented by education brochure.4 The nurse will fit a comfortable continuous positive
      airway pressure (CPAP) mask from a wide range of selection for the patient, who will then be
      given a short trial of continuous positive airway pressure (CPAP) therapy with the Autoset
      (Resmed, Sydney, Australia) continuous positive airway pressure (CPAP) device for those in
      the therapeutic continuous positive airway pressure (CPAP) arm for approximately 30 minutes
      for acclimatization in the afternoon. Attended continuous positive airway pressure (CPAP)
      titration will be performed with the Autoset auto-titrating device on the second night of the
      PSG study for the group randomized to the therapeutic continuous positive airway pressure
      (CPAP) arm.2-4 All the patients in the therapeutic continuous positive airway pressure (CPAP)
      arm will be prescribed the Horizon LT 8001 continuous positive airway pressure (CPAP) device
      (De Vilbiss, Somerset, PA, USA) with a time counter recording machine run time. The
      continuous positive airway pressure (CPAP) 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 (CPAP) titration study.

      The patients randomized to the subtherapeutic continuous positive airway pressure (CPAP) arm
      will have the CPAP units set to the lowest pressure (4 cm of water pressure) and 6 extra 4mm
      holes will be inserted in the collar of the main tubing at the end of the mask to allow air
      escape and to prevent carbon dioxide rebreathing.8,9 They will be given a trial of 30 minutes
      for acclimatization before starting continuous positive airway pressure (CPAP) at home.

      All the patients in each arm will be followed up at the Respiratory clinic separately at 1
      month and 3 months and the objective continuous positive airway pressure (CPAP) compliance
      will be measured from the time counter. Although the 2 different treatment arms are explained
      in the patient information, the patients will not be aware of whether they are receiving
      therapeutic or sham continuous positive airway pressure (CPAP). 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.9 At the end of the study (ie 3 months), all
      patients in the subtherapeutic continuous positive airway pressure (CPAP) arm will be
      readmitted for AutoSet continuous positive airway pressure (CPAP) titration to establish
      their long-term therapeutic pressure.

      Other outcome assessment:

      Prior to commencement of nasal therapeutic or sham continuous positive airway pressure
      (CPAP), all patients have to go through several measurements. These include assessment of
      subjective sleepiness with the Epworth sleepiness scale (ESS)10, quality of life with the
      Calgary Sleep Apnea Quality of Life Index (SAQLI).11 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 24.10 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. The Sleep Apnea Quality of Life Index (SAQLI) has a
      high degree of internal consistency, face validity as judged by content experts and patients
      and construct validity as shown by its positive correlations with the Short Form-36 Health
      Survey questionnaire (SF-36) and the improvement in scores in patients successfully
      completing a 4 weeks' trial of continuous positive airway pressure (CPAP).11 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, and has been applied previously in our Chinese
      obstructive sleep apnea (OSA) patients on continuous positive airway pressure (CPAP). 4 All
      patients will have to complete the Epworth Sleepiness Score (ESS) and Sleep Apnea Quality of
      Life Index (SAQLI) at baseline, 1 month and 3 months after treatment.
    

Intervention name(s): Continuous positive airway pressure (CPAP); Sham Continuous positive airway pressure (CPAP)
Intervention type(s): Device; Device
Intervention description(s): Continuous positive airway pressure (CPAP) - Horizon LT 8001 Continuous positive airway pressure (CPAP) device.; Sham Continuous positive airway pressure (CPAP) - Continuous positive airway pressure (CPAP) units set to the lowest pressure (4 cm of water pressure) and 6 extra 4mm holes will be inserted in the collar of the main tubing at the end of the mask to allow air escape and to prevent carbon dioxide rebreathing.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment