The Obesity-hypoventilation Syndrome Study of Clinical Characteristics and Predictive Factors of Response to Treatment
Condition: Obesity Hypoventilation Syndrome
MeSH terms: Hypoventilation; Obesity Hypoventilation Syndrome; Obesity; Syndrome
Study type: Interventional

Summary: 
      Main objective:

      To describe clinical and functional characteristics of the obese hypoventilating patient; to
      study the relation between the obesity-hypoventilation syndrome (OHS) and the obstructive
      sleep apnea hypopnea syndrome (OSAHS). In the second stage of the study, to assess patient
      response to non-invasive mechanical ventilation (NIV) and continuous positive airway pressure
      (CPAP), and to identify predictors of unfavourable response to treatment.

      Methodology:

        -  Patients: Patients with obesity degree I-III, with pCO2 awake and at rest > 45 mmHg,
           with no underlying pulmonary or neuromuscular lung disease; two control groups, one of
           non-hypoventilating obese patients and the other of obese patients with OSAHS, will also
           be studied over the same period.

        -  Design: Prospective observational study. In the first stage anthropometric, clinical,
           functional and metabolic data will be recorded for the obese hypoventilating patients
           and the two control groups (obese patients without respiratory pathology, and obese
           patients with OSAHS).

      In the second stage patients with OHS will be divided into two subgroups: group 1: patients
      with polysomnography (PSG) suggestive of hypoventilation, in whom NIV treatment will be
      initiated; group 2: patients with PSG suggestive of OSAHS (apnea-hypopnea index >15), who
      will be administered CPAP. Patients will be examined one month and three months after the
      start of treatment. The same measurements will be carried out as at the beginning of the
      study, with the exception of the polysomnographic study. Nonetheless, pulse oximetry and
      arterial gases will be performed on waking.

      Expected Results:

      Patients with OHS may be characterized and differentiated from obese patients without
      associated respiratory pathology on the basis of clinical, functional and metabolic data.

      There is a group of patients with association between OSAHS and OHS that do not respond to
      treatment with CPAP, and this unfavorable response can be predicted in advance.
    

Detailed description: 
      HYPOTHESIS:

      Patients with OHS may be characterized and differentiated from obese patients without
      associated respiratory pathology on the basis of clinical, functional and metabolic data.

      There is a close relation between OHS and OSAHS. It is important to define this relation more
      precisely because of its implications for therapy.

      There is no consensus on the best ventilatory method for the treatment of OHS. In the case of
      an association between OSAHS and OHS the International Consensus proposes initial use of
      CPAP, based on empirical data. We believe that there is a group of patients that do not
      respond to this treatment and that this unfavorable response can be predicted in advance.

      OBJECTIVES:

        -  To assess the clinical, functional and metabolic characteristics of the patient with
           obesity hypoventilation syndrome (OHS).

        -  To describe the frequency and characteristics of the relation between OHS and the
           obstructive sleep apnea hypopnea syndrome (OSAHS).

        -  To study the predictive factors of the response to treatment with CPAP in patients with
           OHS and associated OSAHS.

      METHODOLOGY STUDY SETTING: Pneumology and Endocrinology Services at the Hospital de la Santa
      Creu i Sant Pau. Hospitalization Unit, Sleep Clinic and Pulmonary Function Laboratory.

      PATIENTS: Patients from a conventional hospitalization unit, semi-critical care unit,
      Endocrinology Clinic, Pneumology Clinic and/or Sleep Clinic meeting the following criteria:

        -  Obesity degree I-III (Body mass index, BMI >30 Kg/m2)

        -  Stable daytime PCO2 >45 mmHg.

        -  Age < 75 years

        -  Absence of other parenchymal, respiratory or neuromuscular diseases, diseases of the
           chest wall which may occur concomitantly with hypoventilation.

        -  Absence of exclusion criteria.

      Exclusion criteria:

        -  Cognitive disorders that interfere with the administration of the clinical
           questionnaires.

        -  Grave comorbidity.

        -  FEV1/FVC ratio < 65% in the forced spirometry.

      CONTROL GROUP:

      In parallel, two control groups will be studied:

        -  A group of obese patients with similar age, sex and BMI. Subjects will be included if
           their pCO2< 45 mmHg and if the nocturnal pulse oximetry and specific clinical
           questionnaire are not suggestive of OSAHS.

        -  A group of obese patients with the same characteristics as above, but with diagnosis of
           OSAHS by polysomnograph or polygraph study.

      STUDY VARIABLES:

        -  Anthropometric and socio-demographic data: age, sex, weight, height, BMI, waist
           circumference (above the iliac crest), neck diameter. Age of onset of obesity and length
           of period of obesity.

        -  General clinical questionnaire: family history, history of episodes of acute respiratory
           insufficiency, cardiovascular risk factors and comorbidity.

        -  Subjective assessment of degree of sleepiness: analysed using the Epworth scale (MW
           Johns, Sleep 1991, 14;540).

        -  Degree of sleepiness according to the definition of the American Thoracic Society:
           classification in four categories: absent, mild, moderate and grave.

        -  Study of respiratory function:

        -  Forced spirometry and inspirometry. Maximum F/V loop performed with datapir 500
           spirometer (SIBEL, Barcelona), in accordance with the norms and reference values of the
           SEPAR (Roca et al. Respir Med. 1998 Mar;92(3):401-7.

        -  Static lung volumes. Measured in accordance with the norms and reference values of the
           SEPAR (Roca et al. Respir Med 1998 Mar;92(3):454-60.

        -  Arterial gases at rest. Maximum respiratory pressures (PIMAX, PEMAX): using the method
           described by Morales P. et al (Arch de Bronconeumol 1998; 34: 142-151)

        -  Conventional polysomnography (PSG). PSG will be performed during an entire night using
           Siesta, Compumedics equipment, recording two channels of the electroencephalogram,
           electrooculogram, electromyogram of chin muscles, hemoglobin saturation by pulse
           oximetry, oro-nasal flow by means of thermistor, thoracic and abdominal movements,
           electrocardiogram, anterior tibial electromyogram and body position. Sleep staging will
           be manual, following the classical criteria of Rechschaffen & Kales. The minimum
           recording time will be 6 hours, and the total time of minimal sleep will be 3 hours.

      Definition of apnea: absence of flow for at least 10 s. Definition de hypopnea: any reduction
      in the flow of at least 10 s, accompanied by a desaturation (a noticeable fall in saturation
      with rapid recovery) and/or transitory waking or arousal (defined according to the ASDA
      criteria: Sleep, 1992; 15: 173-184). Definition of hypoventilation: Prolonged periods of
      arterial desaturation not preceded by episodes of respiratory events.

      The following data will be recorded: number of apnea/hypopnea episodes per hour (IAH),
      percentage of time in apnea and/or hypopnea, number of arousals/hour, sleep efficiency (total
      sleep time /length of recording), percentage of time in phases 1, 2, 3-4 and REM, initial
      saturation, mean saturation, minimal saturation, time with saturation below 90% (CT90).

        -  Radioimmunoassay determination of the level of leptin in serum, determination of
           baseline insulinemia, determination of TSH, lipids study (triglycerides, cholesterol
           (total cholesterol, HDL, VDL, LDL, Apo-B)

        -  Adjustment of the optimal level of CPAP: after a second conventional polysomnography
           study, the optimal level of CPAP will be adjusted in the patients who present an IAH >15
           on conventional polysomnography.

        -  Questionnaire on compliance with, and side effects of, CPAP/VNI treatment.

      PROCEDURE:

      First phase: All patients from the semicritical unit, conventional ward, pneumology
      outpatient service and the Sleep Clinic who meet the entry requirements will be included.
      Patients recruited in acute phase will be placed in the pre-inclusion group and will be
      definitively included in the study once their condition has been stable for 6 weeks.

      A sample of obese control patients (BMI>30 Kg/m2 and pCO2 below 45 mmHg), who do not present
      the exclusion criteria described above, will be recruited.

      RECRUITMENT PERIOD: At the start of the recruitment period the patients will be informed of
      the nature of the study and will be asked to give written consent to participate. Then, the
      data on the study variables will be compiled: anthropometric and sociodemographic data,
      general and specific clinical questionnaire, degree of sleepiness, study of respiratory
      function, leptin, baseline insulinemia, and conventional polysomnography.

      In the control patients polysomnography will be performed if they present clinical symptoms
      suggestive of OSAHS or hypoventilation and/or CT 90 > 1% on the nocturnal ambulatory oximetry
      (L. Hernandez Plaza et al. Eur Resp J 1996; 9:74S).

      Second phase: After the polysomnographic study two population groups will be defined: Group
      1: OHS patients: polysomnographic study suggestive of hypoventilation without associated
      OSAHS.

      Group 2: Patients with OHS and OSAHS: polysomnographic study suggestive of hypoventilation
      associated with OSAHS: IAH>15, with a predominance of obstructive events (>50%).

      Patients in group 1 (patients with OHS) will begin NIV treatment, using a BIPAP ventilator in
      Spont/timed mode (RF 12) and nasal masks. The parameters of the respirator will be adjusted
      during a nap; expiratory pressure (EPAP) will be at least 4 cm H2O and inspiratory pressure
      10-20 cm H2O, depending on the patient's tolerance. Oxygen will be added until a continuous
      saturation of between 93-95% is obtained, and a gas sample will be taken on waking.

      In patients in group 2 a CPAP titration study will be carried out. The pressure will be
      adjusted on the basis of a new polysomnographic study. Once the optimum pressure is
      established, a nocturnal pulse oximetry will be performed and arterial gases assessed on
      waking.

      Treatment response will be considered inadequate and the CPAP treatment discontinued during
      the night of titration if:

        -  Patients' tolerance of treatment is poor.

        -  There is no correction of obstructive events and/or episodes of hypoventilation.

      In this case NIV treatment will be initiated, following the procedure described in group 1.

      FOLLOW-UP:

      T1: One month after the beginning of treatment with CPAP/VNI. Patients will be administered a
      questionnaire assessing clinical symptoms, compliance and side effects of treatment, physical
      examination, and arterial gases at rest.

      T3: After three months the same measurements will be carried out as at the beginning of the
      study, with the exception of the polysomnographic study. Nonetheless, pulse oximetry and
      arterial gases will be performed on waking, using the treatment method assigned.

      All patients who present clinical or gasometric deterioration during follow-up requiring a
      change of treatment will be excluded.

      STATISTICAL ANALYSIS:

      Initially, univariate analysis will be performed on the variables recorded in the patients
      and control groups. The results of the categorical variables will be expressed in percentages
      and those of the continuous variables as means + standard deviation, as median or range
      depending on the form of their distribution. Groups will be compared with the chi-squared
      text or through means comparison as required. Subsequently, the variables for which relations
      are found and those considered clinically important will be included in the multivariate
      logistical regression model in order to determine a predictive model of the presence of
      hypercapnia.

      In the second stage of the study, over a 12-week period, the baseline and final scores of the
      variables will be compared using the most suitable statistical test. A p value < 0.05 will be
      considered significant.

      The same analysis will be conducted to evaluate the relation between the different variables
      and the presence of OSAHS.
    

Intervention name(s): CPAP; Bilevel Support Ventilation (Non-Invasive Ventilation)
Intervention type(s): Device; Device
Intervention description(s): Before and after effect of treatment with CPAP; before/after effect of Bilevel support ventilation
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Obesity Hypoventilation syndrome; cytokines; Adipokines; continuous positive airway pressure; bilevel support ventilation; Response to continuous positive airway pressure