Sleep Apnea in Sickle Cell Disease (DREPAPNEE)

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

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.

Study Overview

• Status: Terminated
• 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

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69008
    • Centre Leon Berard
  • Lyon, France, 69003
    • Hopital Edouard Herriot
  • Lyon, France, 69317
    • Hôpital de La Croix Rousse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SS patients; 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; Measurement of the Apnea/hypopnea index (AHI) and oxygen saturation; Biological: calculation of VOC frequency between the first polysomnography and the end of the first year of continuous positive airway pressure treatment; calculation of VOC rate within the two previous years or between first polysomnography and one year of continuous positive airway pressure treatment; Biological: Blood samples; Blood samples with measurements of hematological, hemorheological, inflammatory and blood coagulation markers; Other: Physiological measurements; Evaluation of microvascular reactivity and autonomic nervous system activity
Experimental: SS patients apneic; 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; Measurement of the Apnea/hypopnea index (AHI) and oxygen saturation; Biological: calculation of VOC frequency between the first polysomnography and the end of the first year of continuous positive airway pressure treatment; calculation of VOC rate within the two previous years or between first polysomnography and one year of continuous positive airway pressure treatment; Biological: Blood samples; Blood samples with measurements of hematological, hemorheological, inflammatory and blood coagulation markers; Other: Physiological measurements; Evaluation of microvascular reactivity and autonomic nervous system activity; Other: Continuous Positive Airway Pressure; Continuous Positive Airway Pressure during 1 year

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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

General Publications

• Stauffer E, Poutrel S, Cannas G, Gauthier A, Fort R, Bertrand Y, Renoux C, Joly P, Boisson C, Hot A, Peter-Derex L, Pialoux V, PetitJean T, Connes P. Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease. Front Physiol. 2021 Sep 24;12:743399. doi: 10.3389/fphys.2021.743399. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2018
• Primary Completion (Actual): November 29, 2021
• Study Completion (Actual): November 29, 2021

Study Registration Dates

• First Submitted: November 20, 2018
• First Submitted That Met QC Criteria: November 23, 2018
• First Posted (Actual): November 27, 2018

Study Record Updates

• Last Update Posted (Actual): December 28, 2022
• Last Update Submitted That Met QC Criteria: December 23, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: vaso-occlusive crisis; sickle cell disease; obstructive sleep apnoea
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Sleep Apnea Syndromes; Anemia, Sickle Cell
• Other Study ID Numbers: 69HCL17_0784; 2017-A03352-51 (Other Identifier: ANSM number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No