Sleep Apnea in Sickle Cell Disease

Study Overview
=================
Brief Summary
-----------------
Despite the fact that obstructive sleep apnoea (OSA) is highly prevalent in the sickle cell population, studies focusing on the associations of the two diseases and their common pathophysiological mechanisms are scarce. OSA is one of the most common conditions responsible for hemoglobin desaturation. The nocturnal hemoglobin desaturation occurring in some sickle cell disease (SCD) patients with OSA could trigger hemoglobin S polymerization and red blood cell (RBC) sickling, leading to further blood rheological alterations, hence increasing the risks for VOC. Moreover, OSA has been demonstrated to increase oxidative stress and inflammation in non Sickle Cell Disease (SCD) patients, which, in SCD patients, could increase the risk for complications. Finally, OSA is accompanied by impaired vascular function and autonomic nervous system dysfunction in the general population. Indeed, the presence of OSA in SCD could increase the clinical severity of patients and the frequency of VOC.

Official Title
-----------------
Effects of Obstructive Sleep Apnea on the Frequency of Vaso-occlusive Crises Events and Bio-physical Markers in Sickle Cell Disease

Conditions
-----------------
Sickle Cell Disease

Intervention / Treatment
-----------------
* Diagnostic Test: polysomnography and oxygen saturation exam
* Biological: calculation of VOC frequency between the first polysomnography and the end of the first year of continuous positive airway pressure treatment
* Biological: Blood samples
* Other: Physiological measurements
* Other: Continuous Positive Airway Pressure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Homozygous HbS (Hemoglobin S) (SS) patients, aged between 15 and 3 months and 50 years old, in steady state (i.e. without vaso-occlusive crisis or recent blood transfusion), followed by the sickle cell center of the Hospices Civils de Lyon, and showing symptoms of OSA. Exclusion Criteria: Patients receiving treatment of OSA, recent blood transfusion (less than 2 months), patients not at steady state (VOC or acute chest syndrome less than 2 months), pregnancy.

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SS patients<br>Homozygous sickle cell patients Each patient will undergo the following: polysomnography and oxygen saturation exam calculation of VOC rate within the two previous years Blood samples Physiological measurements | Diagnostic Test: polysomnography and oxygen saturation exam<br>* Measurement of the Apnea/hypopnea index (AHI) and oxygen saturation<br>Biological: calculation of VOC frequency between the first polysomnography and the end of the first year of continuous positive airway pressure treatment<br>* calculation of VOC rate within the two previous years or between first polysomnography and one year of continuous positive airway pressure treatment<br>Biological: Blood samples<br>* Blood samples with measurements of hematological, hemorheological, inflammatory and blood coagulation markers<br>Other: Physiological measurements<br>* Evaluation of microvascular reactivity and autonomic nervous system activity<br>|
| Experimental: SS patients apneic<br>Homozygous sickle cell patients after one year of continuous positive airway pressure treatment Each patient will undergo the following: polysomnography and oxygen saturation exam calculation of VOC rate within the two previous years Blood samples Physiological measurements | Diagnostic Test: polysomnography and oxygen saturation exam<br>* Measurement of the Apnea/hypopnea index (AHI) and oxygen saturation<br>Biological: calculation of VOC frequency between the first polysomnography and the end of the first year of continuous positive airway pressure treatment<br>* calculation of VOC rate within the two previous years or between first polysomnography and one year of continuous positive airway pressure treatment<br>Biological: Blood samples<br>* Blood samples with measurements of hematological, hemorheological, inflammatory and blood coagulation markers<br>Other: Physiological measurements<br>* Evaluation of microvascular reactivity and autonomic nervous system activity<br>Other: Continuous Positive Airway Pressure<br>* Continuous Positive Airway Pressure during 1 year<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of VOC crises required hospitalization in the previous two years | Calculated over a 2 years period before inclusion. VOC requiring hospitalizations will be recorded. Measured at day 1 | day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood inflammatory markers | Blood inflammatory markers : C Reactive Protein (CRP, mg/L) The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Blood inflammatory markers | Blood inflammatory markers : C Reactive Protein (CRP, mg/L) | Day 365 | 
| Markers of blood coagulation | Biological risk factors of VOC : prothrombin time (PT, s), D-dimer (µg/L), Fibrinogen (g/L), Activated Thromboplastin Time (APPT, s), protein C and protein S (%) The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Markers of blood coagulation | prothrombin time (PT, s), D-dimer (µg/L), Fibrinogen (g/L), Activated Thromboplastin Time (APPT, s), protein C and protein S (%) | Day 365 | 
| Blood cell counts and markers of hemolysis | Biological risk factors of VOC : Blood cell counts and markers of hemolysis : red blood cell count (G/L), neutrophil count (G/L), hemoglobin concentration (g/dL), hematocrit (%), mean corpuscular volume (MCV, fl), mean corpuscular hemoglobin concentration (MCHC, pg), platelet count (G/L), lactate dehydrogenase (LDH, IU), bilirubin (µg/L), aspartate transaminase (AST, U/L). The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Blood cell counts and markers of hemolysis | Blood cell counts and markers of hemolysis : red blood cell count (G/L), neutrophil count (G/L), hemoglobin concentration (g/dL), hematocrit (%), mean corpuscular volume (MCV, fl), mean corpuscular hemoglobin concentration (MCHC, pg), platelet count (G/L), lactate dehydrogenase (LDH, IU), bilirubin (µg/L), aspartate transaminase (AST, U/L). | Day 365 | 
| Markers of nitric oxide metabolism | Biological risk factors of VOC : markers of nitric oxide production nitrites, nitrate, nitrotyrosine The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Markers of nitric oxide metabolism | markers of nitric oxide production nitrites, nitrate, nitrotyrosine | Day 365 | 
| Oxidative stress markers | Biological risk factors of VOC : protein oxidation marker (advanced oxidation protein products), markers of lipid peroxidation (malondialdehyde), antioxidant enzymatic activities (super oxide dismutase, catalase, glutathione peroxidase), antioxidant power (ferric reducing ability of plasma) The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Oxidative stress markers | protein oxidation marker (advanced oxidation protein products), markers of lipid peroxidation (malondialdehyde), antioxidant enzymatic activities (super oxide dismutase, catalase, glutathione peroxidase), antioxidant power (ferric reducing ability of plasma) | Day 365 | 
| Hemorheological parameters | blood viscosity (cP) measured with a cone plate viscometer at several shear rates, red blood cell deformability (a.u) measured by ektacytometry at several shear stresses, red blood cell aggregation (%) properties measured by laser backscatter method. The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Hemorheological parameters | Biological risk factors of VOC : blood viscosity (cP) measured with a cone plate viscometer at several shear rates, red blood cell deformability (a.u) measured by ektacytometry at several shear stresses, red blood cell aggregation (%) properties measured by laser backscatter method. | Day 365 | 
| Arterial blood gases | Biological risk factors of VOC : oxygen and carbon dioxide pressure (mmHg), pH The morning after the polysomnography blood samples will be collected (M1 +/- 15 days) | An average of 1 month | 
| Arterial blood gases | oxygen and carbon dioxide pressure (mmHg), pH | Day 365 | 
| Vascular function (microvascular reactivity to skin heating test) | Physiological risk factors of VOC : A laser Doppler flowmeter (Periflux 5000 Perimed) will be used to measure skin blood flow in resting condition and during a local thermal hyperemia (LTH) test (temperature will be increased from 33 °C to 42 °C) for 35 min. The peak response during the LTH reflects vasodilatation caused by axonal reflex while the delayed plateau response of the LTH test is mainly dependent on the ability to produce nitric oxide to promote vasodilation. | Day 1 | 
| Vascular function (microvascular reactivity to skin heating test) | A laser Doppler flowmeter (Periflux 5000 Perimed) will be used to measure skin blood flow in resting condition and during a local thermal hyperemia (LTH) test (temperature will be increased from 33 °C to 42 °C) for 35 min. The peak response during the LTH reflects vasodilatation caused by axonal reflex while the delayed plateau response of the LTH test is mainly dependent on the ability to produce nitric oxide to promote vasodilation. | Day 365 | 
| autonomic nervous system activity (measured by heart rate variability analysis) | Physiological risk factors of VOC : electrocardiographic signals acquired by the polysomnographic machine will be extracted and the R-R intervals will be used for time domain spectral analyses to calculate several indices reflecting the activity of the autonomic nervous system activity. The ratio between the low frequency and the high frequency powers (LF/HF) will be used to characterize the autonomic imbalance. | Day 1 | 
| autonomic nervous system activity (measured by heart rate variability analysis) | electrocardiographic signals acquired by the polysomnographic machine will be extracted and the R-R intervals will be used for time domain spectral analyses to calculate several indices reflecting the activity of the autonomic nervous system activity. The ratio between the low frequency and the high frequency powers (LF/HF) will be used to characterize the autonomic imbalance. | Day 365 | 
| Frequency of VOC | Number of VOC requiring hospitalizations during the past year | Day 365 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sickle cell disease, obstructive sleep apnoea, vaso-occlusive crisis