Cerebral Tissue Desaturation in Children with Sickle Cell Disease

Children with sickle cell disease (SCD) frequently suffer silent and overt cerebral infarction. Current screening and prevention techniques are suboptimal. Absolute cerebral oximetry is a rapid, non-invasive technique to measure hemoglobin (Hb) saturation in the brain. Cerebral tissue Hb saturation (S_CTO₂) is a physiologic measurement of the balance between oxygen supply and demand that could be used to identify regions of the brain at highest risk of infarction. We aimed to describe the distribution of S_CTO₂ in children with SCD and to identify its relationships with clinical, laboratory, and neuroimaging characteristics as well as response to transfusion.

We used transcutaneous near-infrared spectrophotometry (CASMED FORE-SIGHT®) with bi-frontal probes to measure absolute S_CTO₂ in children with sickle cell anemia (SS), sickle-β⁰-thalassemia (Sβ⁰), sickle hemoglobin C disease (SC), and sickle-β⁺-thalassemia (Sβ⁺) during steady-state clinic visits or at the time of transfusion for stroke prophylaxis. Spearman correlation and multivariable modeling were used to test the relationships between S_CTO₂ and age, sex, genotype, Hb concentration, percent Hb F, percent reticulocytes, peripheral Hb saturation (S_PO₂), and cerebral arterial blood flow velocities by transcranial Doppler ultrasonography (TCD).

We studied 149 children (112 SS/Sβ⁰; 37 SC/Sβ⁺) with a mean age of 6.6±4.7 years (±S.D.). S_CTO₂ is known to be 65–80% in normoxic individuals with normal hemoglobin type and concentration breathing room air, but we found S_CTO₂ to be markedly lower in SCD: 53.2±14.2 (mean±SD) in SS/Sβ⁰ and 66.1±9.2% in SC/Sβ⁺ patients. S_CTO₂ was abnormally low (<65%) in 75% of SS/Sβ⁰ and 35% of SC/Sβ⁺ patients. S_CTO₂ correlated significantly with age (Spearman ρ=-0.54, P<0.001), sex (0.38, P<0.001), Hb concentration (0.38, P<0.001), percent reticulocytes (-0.3, P=0.002), percent Hb F (0.37, P<0.001), and S_PO₂ (0.4, P<0.001), but not TCD velocities as continuous measurements. However, when TCD velocities were categorized according to STOP criteria (abnormal and conditional vs. normal), S_CTO₂ was lower when the TCD velocity in the ipsilateral distal internal carotid artery was not normal (right-sided S_CTO₂: 39.2% for abnormal and conditional TCD vs. 57% for normal TCD, P=0.027). In multivariable models, the significant independent determinants of S_CTO₂ were S_PO₂ (P=0.004), Hb concentration (P=0.004), and age (P<0.001). Each unit decrease (1% absolute) in S_PO₂ gave an odds ratio of 1.4 or 1.5 for an abnormally low (<25^th percentile) S_CTO₂ in the left and right hemispheres, respectively (AUC 0.84; P<0.001). Transfusion increased S_CTO₂ by 15.3% (absolute) on the left (P=0.002) and 23.6% (absolute) on the right (P=0.06). Two participants had severe unilateral cerebral vasculopathy demonstrated by magnetic resonance angiography. Both had a lower pre-transfusion S_CTO₂ on the side of the stenosis or occlusion (5-20% lower). The S_CTO₂ rose during the course of transfusion (10-30% absolute rise in S_CTO₂), and by the end of the transfusion the right- and left-sided S_CTO₂ measurements equalized.

Cerebral tissue Hb desaturation is common in children with SCD and more severe in the SS/Sβ⁰ genotypes. Cerebral desaturation is associated with peripheral Hb desaturation, more severe anemia, increasing age, and occlusive vasculopathy, and it is ameliorated by transfusion. Cerebral desaturation, which can be detected rapidly and non-invasively, is a physiologic biomarker of brain at risk for ischemic injury. Cerebral oximetry should be studied further as a physiologic means to predict stroke and guide transfusion therapy for the prophylaxis of stroke in SCD.

No relevant conflicts of interest to declare.