Pathophysiology of Hypoventilation in Obesity and Effects of Bariatric Intervention

Study Overview
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Brief Summary
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Breathing is impacted by obesity. Early changes are characterised by significant breathing abnormalities during sleep (a condition called sleep disordered breathing, the most common of which is obstructive sleep apnoea). As the breathing changes worsen in severity, it may result in a rise in carbon dioxide levels during daytime causing a condition called obesity hypoventilation syndrome (OHS). The current treatment for obesity related breathing changes include supportive breathing therapy at night, optimisation of associated medical conditions and weight loss. Weight management is an important part of obesity treatment. Weight loss strategies such as life-style modification do not always work. Weight loss surgery (bariatric surgery) has been shown to be an effective weight management intervention with long-term results. This study aims to understand breathing changes that occurs due to obesity and their resolution after weight loss surgery. The investigators are aiming to recruit participants with sleep disordered breathing who are currently awaiting bariatric surgery. In particular, the investigators are interested in comparing breathing changes in participants with OHS, who have abnormal regulation of their carbon dioxide levels, and participants with sleep disordered breathing with normal CO2 regulation. Participants will be recruited through outpatient clinics for sleep disordered breathing. The participants will undergo comprehensive breathing assessments on enrolment including an overnight sleep study. Participants will undergo further daytime breathing assessments before and after their bariatric surgery. End of study will be 6 months after surgery - participants will have a final comprehensive breathing assessment including an overnight sleep study to review resolution of their breathing changes. Depending on the wait list time for the bariatric surgery, it is anticipated that participants will be enrolled in the study for 2 years.

Official Title
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Pathophysiology of Hypoventilation in Obesity and Effects of Bariatric Intervention: PHOEBI Study

Conditions
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Obesity Hypoventilation Syndrome (OHS)

Intervention / Treatment
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* Procedure: Bariatric Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years or older BMI > 40 Patients with significant sleep disordered breathing requiring treatment Patient is being assessed for bariatric surgery for either gastric sleeve or gastric bypass surgery Exclusion Criteria: Patients with decompensated hypercapnic respiratory failure (pH< 7.3) Chronic hypercapnic respiratory failure due to a cause other than obesity such as neuromuscular, chest wall or airway disease Unstable cardiac disease including coronary artery disease and heart failure Significant co-morbid psychiatric disease requiring anti-psychotic medications Chronic pain syndrome on high dose opioid medications Treatment for drug or alcohol addiction Cognitive impairment that would prevent informed consent Pregnancy Need for long-term renal replacement therapy Patients who undergo bariatric intervention with gastric balloon or gastric band.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hypercapnic<br>Obese patients with daytime hypercapnia | Procedure: Bariatric Surgery<br>* Weight loss surgery with either gastric sleeve or gastric bypass surgery<br>|
| Eucapnic<br>Obese patients with normal daytime carbon dioxide levels | Procedure: Bariatric Surgery<br>* Weight loss surgery with either gastric sleeve or gastric bypass surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expiratory flow limitation as measured by forced oscillation testing | Measurement of expiratory flow limitation at different position including upright, 45 degrees and supine. We will explore whether expiratory flow limitation can differentiate hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patients has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Degree of change in expiratory flow limitation | Explore whether the degree of positional change in expiratory flow limitation can differentiate between eucapnic and hypercapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Closing capacity | Measurement of closing capacity at different position including upright, 45 degrees and supine. We will explore whether expiratory flow limitation can differentiate hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Degree of change in closing capacity | Explore whether the degree of positional change in closing capacity can differentiate between eucapnic and hypercapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Correlation between closing capacity and expiratory flow limitation | Compare outcome 1 and 3 to explore whether there is a relationship between expiratory flow limitation and closing capacity | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Intra-abdominal pressure | We will measure intra-abdominal pressure and explore whether hypercapnic patients have increased intra-abdominal pressure. Positional changes will be measured | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Correlation between intra-abdominal pressure, closing capacity and expriatory flow limitation | Compare outcome 1,3 and 6. This is a complex multi-compartment model that can differentiate hypercapnia and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Upper airway collapsibility | Measurement of upper airway collapsibility as measure by negative expiratory pressure. Explore whether there is a relationship between hypercapnic and eucapnic patients depending on degree of upper airway collapsibility | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Lung compliance | Measurement of lung compliance with pressure volume curve including measurements in different positions (upright, 45 degrees and supine) | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Respiratory muscle strength (maximal inspiratory pressure/maximal expiratory) | Measurement of inspiratory and expiratory muscle strength | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Respiratory muscle strength (SNIP test) | Measurement of sniff nasal inspiratory pressure | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Daytime neural respiratory drive (para-sternal electromyography measurements) | Daytime neural respiratory drive as measured by parasternal electromyography (EMG) measurements can differentiate between hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Daytime neural respiratory drive (diaphragm electromyography measurements) | Daytime neural respiratory drive as measured by diaphragm electromyography (EMG) measurements can differentiate between hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Nocturnal neural respiratory drive (para-sternal electromyography measurements) | Nocturnal neural respiratory drive as measured by parasternal electromyography (EMG) measurements can differentiate between hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Nocturnal neural respiratory drive (diaphragm electromyography measurements) | Nocturnal neural respiratory drive as measured by diaphragm electromyography (EMG) measurements can differentiate between hypercapnic and eucapnic patients | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Quality of life post bariatric surgery with SF-36 | Quality of life changes after bariatric surgery more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Quality of life post bariatric surgery with EQ-5D | Quality of life changes after bariatric surgery more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Symptom change after commencement of medical therapy compared to bariatric surgery measured with Epworth Sleepiness Scale | Symptom change after bariatric surgery is more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Symptom change after commencement of medical therapy compared to bariatric surgery measured with mMRC (modified medical research council) dypnoea score | Symptom change after bariatric surgery is more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Symptom change after commencement of medical therapy compared to bariatric surgery measured with Multi-dimensional dyspnoea profile | Symptom change after bariatric surgery is more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Symptom change after commencement of medical therapy compared to bariatric surgery measured with Severe Respiratory Insufficiency Questionnaire | Symptom change after bariatric surgery is more than with standard medical therapy | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Changes in healthcare resource usage in OHS patients post bariatric surgery | Estimation of healthcare usage cost in the 6 months prior to surgery and 6 months post surgery including medication costs and re-admissions to hospital | 6 months pre bariatric surgery and 6 months post bariatric surgery | 
| Improvement in daytime CO2 levels | Arterial blood gas performed before and after bariatric surgery with improvement in CO2 levels | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Improvement in apnoea-hyponoea index | Patients will have diagnostic sleep study before and after bariatric surgery | Before bariatric surgery on enrolment and 6 months after bariatric surgery | 
| Improvement in mean nocturnal oxygen saturation during sleep | Patients will have diagnostic sleep study before and after bariatric surgery | Before bariatric surgery on enrolment and 6 months after bariatric surgery | 
| Improvement in mean time spent below 90% oxygen saturation during sleep | Patients will have diagnostic sleep study before and after bariatric surgery | Before bariatric surgery on enrolment and 6 months after bariatric surgery | 
| Changes in sleep architecture measured by %slow wave sleep and %REM sleep | Patients will have diagnostic sleep study before and after bariatric surgery | Before bariatric surgery on enrolment and 6 months after bariatric surgery | 
| Improvement in diaphragm function | Diaphragm thickening will be measured by ultrasound assessment | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery | 
| Improvement in glycaemic control | HbA1C will be measured before and after bariatric surgery | Measurements on enrolment into study; measurements prior to bariatric surgery (once patient has a surgery date); measurements 2-4 weeks after bariatric surgery; and end of study measurements 6 months after bariatric surgery |