The Hematologist

September-October 2019, Volume 16, Issue 5

To Breathe or Not to Breathe... Does It Matter for SCD VOC?

Ifeyinwa (Ify) Osunkwo, MD, MPH Director, Sickle Cell Disease Enterprise
Levine Cancer Institute/Atrium Health, Chapel Hill, NC

Published on: August 06, 2019

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

ClinicalTrials.gov Identifier: NCT03753854

Sponsor: Hospices Civils de Lyon

Accrual Goal: 80 participants

Participating Centers: Hôpital Edouard Herriot, Lyon, France (Giovanna Cannas); Centre Leon Berard, Lyon, France (Alexandra Gauthier); Hôpital de la Croix Rousse, Lyon, France (Emeric Stauffer)

Study Design: This is a prospective nonrandomized parallel assignment intervention trial. The trial will enroll individuals living with sickle cell disease (SCD; homozygous SS genotype only) between age 15 years and three months up to age 50 years and showing signs of obstructive sleep apnea (OSA). This study will exclude individuals already receiving treatment for OSA, those who have had a blood transfusion within two months, are currently pregnant, or who are not at “steady state,” defined as having a vaso-occlusive crisis (VOC) or acute chest syndrome episode within the prior two months. After informed consent, the number of VOCs requiring hospitalization in the previous two years will be abstracted from their medical records prior to initiating study procedures.

Participants will undergo study procedures at baseline and at one-year follow-up. Frequency of VOC over the next year will be assessed prospectively as the primary outcome measure. Study procedures include a polysomnography examination to determine their apnea/hypopnea index (AHI) and oxygen saturation, blood samples, and various assessments to evaluate autonomic function and vascular reactivity.

Participants with elevated AHI will be placed on continuous positive airway pressure (CPAP) and followed prospectively for a year, at which time all baseline assessments will be repeated. The primary objective of this trial is to determine the frequency of VOCs between first polysomnography and the end of the first year of CPAP treatment.

Additional correlative studies will include analysis of hematologic markers including red blood cell (RBC) count, hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, lactate dehydrogenase, bilirubin, and aspartate transaminase; hemorheological parameters including blood viscosity measured by cone plate viscometer at several shear rates, RBC deformability measured by ektacytometry, and RBC aggregation properties measured by laser back-scatter method; the inflammatory marker C-reactive protein; procoagulant markers including prothrombin time, D-dimer, fibrinogen, activated thromboplastin time, protein C, and protein S; and oxidative stress markers, namely advanced oxidation protein products, malondialdehyde, super oxide dismutase, catalase, glutathione peroxidase, and ferric-reducing ability of plasma. An arterial blood gas assessment measuring oxygen and carbon dioxide pressure and pH will also be performed. Vascular function will be measured using a laser Doppler flowmeter to measure skin blood flow in resting condition and via a local hyperthermia test (LTH). The LTH evaluates vasodilation caused by axonal reflex and assesses the ability to produce enough nitric oxide to promote vasodilation. Autonomic nervous system activity will be evaluated using electrocardiographic signals acquired by the polysomnographic machine.

Rationale: The long-term negative impact of OSA on vascular and autonomic nervous system function has been well recognized in the literature, with increasing knowledge of its application and implications for individuals living with SCD.1-3 Comorbid OSA was identified among 21 percent of children with SCD in a retrospective study. These children had 47 percent more health complications and higher rates of complications per year than those without OSA. OSA was associated with intermittent dips of low oxygen levels during sleep, resulting in pulmonary, cardiovascular, neurological, and behavioral morbidities.4

OSA is highly prevalent (40-80% of patients) in the SCD population; however, there remains a gap in the research focusing on the association between OSA and SCD and its consequent impact on short- and long-term morbidity and mortality, particularly among adults.5 Several studies have reported the high prevalence rates of sleep disorders and OSA in adults6 and children with SCD7-9; however, there is a paucity of research on how to mitigate the potential negative consequences of OSA in an individual living with SCD.

This study will explore the impact of CPAP on improving rates of VOC as well as various biologic parameters of disease severity in individuals with SCD and comorbid OSA. It will be the first correlative study of its kind, and results will inform larger intervention studies of CPAP or other treatment modalities to improve OSA. This study will provide evidence to support assessment of OSA treatment efficacy using biologic markers of vascular and autonomic nervous system function.

Comment: This is an ambitious study with numerous secondary endpoints looking at biologic and physiologic correlates of cardiovascular and autonomic function. Importantly, it will examine both adolescents and adults, possibly providing a glimpse into the age-related changes in vascular reactivity and autonomic dysfunction in SCD and its response to CPAP over time.

References

  1. Baltzis D, Bakker JP, Patel SR, et al. Obstructive sleep apnea and vascular diseases. Compr Physiol. 2016;6:1519-1528.
  2. Parish JM, Somers VK. Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc. 2004;79:1036-1046.
  3. Mucenica EC, Boişteanu D, Vasiloiu G, et al. [The influence of nCPAP therapy on the autonomic nervous system dysfunction in OSA patients]. Rev Med Chir Soc Med Nat Iasi. 2007;111:379-382.
  4. Katz T, Schatz J, Roberts CW. Comorbid obstructive sleep apnea and increased risk for sickle cell disease morbidity. Sleep Breath. 2018;22:797-804.
  5. Rogers VE, Lewin DS, Winnie GB, et al. Polysomnographic characteristics of a referred sample of children with sickle cell disease. J Clin Sleep Med. 2010;6:374-381.
  6. Sharma S, Efird JT, Knupp C, et al. Sleep disorders in adult sickle cell patients. J Clin Sleep Med. 2015;11:219-223.
  7. Rosen CL, DeBaun MR, Strunk RC, et al. Obstructive sleep apnea and sickle cell anemia. Pediatrics. 2014;134:273-281.
  8. Wittig RM, Roth T, Keenum AJ, et al. Snoring, daytime sleepiness, and sickle cell anemia. Am J Dis Child. 1988;142:589.
  9. Kaleyias J, Mostofi N, Grant M, et al. Severity of obstructive sleep apnea in children with sickle cell disease. J Pediatr Hematol Oncol. 2008;30:659-665.

Conflict of Interests

Dr. Osunkwo served as a consultant and speaker for Novartis (makers of Jadenu) and Terumo BCT (manufacturer of the Spectrum Optia machine for erythrocytapheresis), is an advisor for Pfizer, and is on the Data and Safety Monitoring Board for Micelle Biopharma. back to top