Continuous Positive Pressure Versus Bi-level in Overlap Syndrome

Study Overview
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Brief Summary
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Continuous positive airway pressure (CPAP) became the established treatment for overlap syndrome (OS). It has been showed that the survival benefits of CPAP favored hypercapnic patients. When considering hypercapnic stable COPD patients, survival benefits occurred when the use of bi- level ventilation therapy was targeted to significantly reduce hypercapnia. This highlights the relevance of hypercapnia and hypoventilation correction. Thus, the purpose of this study is to compare the use of CPAP to Bi-level ventilation in hypercapnic OS patients, since the later may correct not only the airway patency but also increase the magnitude of each breath.

Detailed Description
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Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) represent two of the most prevalent respiratory disorders in clinical practice and their coexistence is often described has overlap syndrome (OS) In patients with COPD, the coexistence of OSA is associated with an increased risk of death from any cause, and hospitalization because of COPD exacerbation. Treatment with continuous positive airway pressure (CPAP) has been showed to be effective and associated with improved survival and decreased hospitalizations. When CPAP became established treatment for overlap syndrome, a multivariate analysis revealed that the hours of CPAP use were an independent predictor of mortality. Furthermore, it has been showed that the survival benefit of CPAP favors hypercapnic patients with overlap syndrome. Regarding hypercapnic stable COPD patients, the best results with long-term non-invasive positive pressure ventilation have been noted in studies using more intensive strategies of ventilation, with higher inspiratory pressures and higher backup rates that improved or even normalized daytime hypercapnia. In fact, survival benefits occurred when ventilation was targeted to significantly reduce hypercapnia. As for typical COPD, overlap syndrome patients might also benefit from optimal daytime hypercapnia correction, which could be better achieved using bi-level ventilation instead of CPAP, since it could not only maintain airway patency but also improve alveolar ventilation. This study aims to compare CPAP therapy to bi-level ventilatory support in overlap syndrome patients, not only for the efficacy to achieve hypercapnia reduction, but also regarding acute disease exacerbations, symptoms and treatment compliance. Therefore, the authors designed a randomized controlled trial with recruitment and power calculations based on the applicant's own data. After the diagnosis, patients will be randomized either for CPAP or BPAP treatment. If CPAP is to be initiated, optimal pressure to maintain upper airway patency will be determined. If there are continued obstructive respiratory events at 15 cm H2O of CPAP, patients will cross-over to the BPAP study arm. Regarding BPAP titration, patients will be treated with ventilators set in pressure support spontaneous/timed mode, both inspiratory and expiratory positive airway pressures (IPAP and EPAP) will be manually titrated. EPAP will ensure optimal pressure for maintaining upper airway patency and IPAP will be defined according to patient tolerance and pressure support necessary to achieve normal PaCO2 values or to reduce baseline PaCO2 by 20% or more; Follow-up will be performed at 1, 6 and 12 months. Follow-up will include clinical evaluation with physical examination and questionnaires (COPD Assessment test, Epworth Sleepiness Scale and MRC dyspnea score), blood gas analysis, treatment adherence, AHI, nocturnal pulse oximetry and exacerbations. 12-month follow-up will also include lung function test, 6-min walking test and nocturnal capnography.

Official Title
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Optimal Positive Airway Pressure in Overlap Syndrome: a Randomized Controlled Trial

Conditions
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Overlap Syndrome, Nocturnal Hypoventilation

Intervention / Treatment
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* Device: Bi-level positive airway pressure with ventilatory support
* Device: continuous positive airway pressure without ventilatory support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COPD (FEV1/FVC < 70 (post-BD) and history of smoking - 10 PPY) FEV1< 80% and COPD symptoms AHI ≥ 15 events/hour Exclusion Criteria: Persistent hypercapnic respiratory failure with acidosis (defined as pH <7.30 after bronchodilators) Hypoxia requiring long term oxygen therapy BMI > 35 kg/m2 Previously-initiated long term non-invasive positive pressure ventilation Other lung disease resulting in respiratory symptoms Age <40 years Pregnancy Malignant comorbidities Patients undergoing renal replacement therapy Restrictive lung disease causing hypercapnia Severe heart failure, unstable angina and severe arrhythmias Inability to comply with the protocol

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized controlled trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CPAP<br>Oronasal CPAP therapy applied as per current international guidelines | Device: continuous positive airway pressure without ventilatory support<br>* Continuous positive airway pressure (CPAP) will be applied in the active comparator group through a oronasal interface.<br>|
| Experimental: Bi-level<br>Oronasal Bi-level therapy + supplemental oxygen (if necessary) applied as per current international guidelines | Device: Bi-level positive airway pressure with ventilatory support<br>* Positive airway pressure will be applied in the experimental group through a oronasal interface, in ventilatory support mode (Bi-level) with a fixed backup rate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| diurnal hypercapnia (pCO2 <= 45 mmH2O ) | (PaCO2 <= 45 mmH2O ) | 1 year | 
| nocturnal oxygen desaturation correction | Mean nocturnal SpO2 >=90%, with <10% of the total recording time <90% after correction of leaks) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in FEV1 | Forced Expiratory Volume (FEV1) in first second (% of predicted) from pre-intervention to follow up | 1 year | 
| Changes in FVC | Forced vital capacity (FVC) (% of predicted) from pre-intervention to follow up | 1 year | 
| Changes in RV | Residual volume (RV) (% of predicted) from pre-intervention to follow up | 1 year | 
| exercise tolerance | Change in the 6 minute walking test from pre-intervention to follow up | 1 year | 
| Sleepiness evaluation | Epworth sleepiness scale is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'. Comparation of patient score from pre-intervention to follow up | 1 year | 
| acute respiratory exacerbations | Frequency of acute exacerbations of COPD requiring addition of antibiotics and or steroids and or hospital admission | 1 year | 
| Compliance to PAP | median hours of compliance per night | 1 year | 
| PAP usage | percentage of days of use per month | 1 year | 
| Dyspnoea evaluation | The mMRC Dyspnea Scale quantifies disability attributable to breathlessness and is useful for baseline dyspnea characterization in patients with respiratory diseases. The score can range from 0 to 4. The higher the mMRC score the higher the dyspnea. Comparation of patient score from pre-intervention to follow up | 1 year | 
| Symptoms of COPD | COPD Assessment test | 1 year | 
| Apneia/Hiponeia Index | Number of Residual AHI/per hour | 1 year | 
| nocturnal hypoventilation | ∆PtcCO2<10mmHg during night from pre-intervention to follow up | 1 year |